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PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-.

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Genetics of Prostate Cancer (PDQ®)

Health Professional Version

.

Published online: October 2, 2015.

Created: .

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: Many of the genes described in this summary are found in the Online Mendelian Inheritance in Man (OMIM) database. When OMIM appears after a gene name or the name of a condition, click on OMIM for a link to more information.]

The public health burden of prostate cancer is substantial. A total of 220,800 new cases of prostate cancer and 27,540 deaths from the disease are anticipated in the United States in 2015, making it the most frequent nondermatologic cancer among U.S. males.[1] A man’s lifetime risk of prostate cancer is one in seven. Prostate cancer is the second leading cause of cancer death in men, exceeded only by lung cancer.[1]

Some men with prostate cancer remain asymptomatic and die from unrelated causes rather than as a result of the cancer itself. This may be due to the advanced age of many men at the time of diagnosis, slow tumor growth, or response to therapy.[2] The estimated number of men with latent prostate carcinoma (i.e., prostate cancer that is present in the prostate gland but never detected or diagnosed during a patient’s life) is greater than the number of men with clinically detected disease. A better understanding is needed of the genetic and biologic mechanisms that determine why some prostate carcinomas remain clinically silent, while others cause serious, even life-threatening illness.[2]

Prostate cancer exhibits tremendous differences in incidence among populations worldwide; the ratio of countries with high and low rates of prostate cancer ranges from 60-fold to 100-fold.[3] Asian men typically have a very low incidence of prostate cancer, with age-adjusted incidence rates ranging from 2 to 10 cases per 100,000 men. Higher incidence rates are generally observed in northern European countries. African American men, however, have the highest incidence of prostate cancer in the world; within the United States, African American men have a 60% higher incidence rate than white men.[4]

These differences may be due to the interplay of genetic, environmental, and social influences (such as access to health care), which may affect the development and progression of the disease.[5] Differences in screening practices have also had a substantial influence on prostate cancer incidence, by permitting prostate cancer to be diagnosed in some patients before symptoms develop or before abnormalities on physical examination are detectable. An analysis of population-based data from Sweden suggested that a diagnosis of prostate cancer in one brother leads to an early diagnosis in a second brother using prostate-specific antigen (PSA) screening.[6] This may account for an increase in prostate cancer diagnosed in younger men that was evident in nationwide incidence data. A genetic contribution to prostate cancer risk has been documented, but knowledge of the molecular genetics of prostate cancer is still limited. Malignant transformation of prostate epithelial cells and progression of prostate carcinoma are likely to result from a complex series of initiation and promotional events under both genetic and environmental influences.[7]

Risk Factors for Prostate Cancer

The three most important recognized risk factors for prostate cancer in the United States are:

Age

Age is an important risk factor for prostate cancer. Prostate cancer is rarely seen in men younger than 40 years; the incidence rises rapidly with each decade thereafter. For example, the probability of being diagnosed with prostate cancer is 1 in 304 for men 49 years or younger, 1 in 44 for men aged 50 through 59 years, 1 in 16 for men aged 60 through 69 years, and 1 in 9 for men aged 70 years and older, with an overall lifetime risk of developing prostate cancer of 1 in 7.[1]

Race

The risk of developing and dying from prostate cancer is dramatically higher among blacks, is of intermediate levels among whites, and is lowest among native Japanese.[8,9] Conflicting data have been published regarding the etiology of these outcomes, but some evidence is available that access to health care may play a role in disease outcomes.[10]

Family history of prostate cancer

As with breast and colon cancer, familial clustering of prostate cancer has been reported frequently.[11-15] From 5% to 10% of prostate cancer cases are believed to be primarily caused by high-risk inherited genetic factors or prostate cancer susceptibility genes. Results from several large case-control studies and cohort studies representing various populations suggest that family history is a major risk factor in prostate cancer.[12,16,17] A family history of a brother or father with prostate cancer increases the risk of prostate cancer, and the risk is inversely related to the age of the affected relative.[13-17] However, at least some familial aggregation is due to increased prostate cancer screening in families thought to be at high risk.[18]

Although many of the prostate cancer studies examining risks associated with family history have used hospital-based series, several studies described population-based series.[19-21] The latter are thought to provide information that is more generalizable. A meta-analysis of 33 epidemiologic case-control and cohort-based studies has provided more detailed information regarding risk ratios related to family history of prostate cancer. Risk appeared to be greater for men with affected brothers than for men with affected fathers in this meta-analysis. Although the reason for this difference in risk is unknown, possible hypotheses have included X-linked or recessive inheritance. In addition, risk increased with increasing numbers of affected close relatives. Risk also increased when a first-degree relative (FDR) was diagnosed with prostate cancer before age 65 years. (See Table 1 for a summary of the relative risks [RRs] related to a family history of prostate cancer.)[22]

Table 1. Relative Risk (RR) Related to Family History of Prostate Cancera

Risk GroupRR for Prostate Cancer (95% CI)
Brother(s) with prostate cancer diagnosed at any age3.14 (2.37–4.15)
Father with prostate cancer diagnosed at any age2.35 (2.02–2.72)
One affected FDR diagnosed at any age2.48 (2.25–2.74)
Affected FDRs diagnosed <65 y2.87 (2.21–3.74)
Affected FDRs diagnosed ≥65 y1.92 (1.49–2.47)
Second-degree relatives diagnosed at any age2.52 (0.99–6.46)
Two or more affected FDRs diagnosed at any age4.39 (2.61–7.39)

CI = confidence interval; FDR = first-degree relative.

aAdapted from Kiciński et al.[22]

Among the many data sources included in this meta-analysis, those from the Swedish population-based Family-Cancer Database warrant special comment. These data were derived from a resource that contained more than 11.8 million individuals, among whom there were 26,651 men with medically verified prostate cancer, of which 5,623 were familial cases.[23] The size of this data set, with its nearly complete ascertainment of the entire Swedish population and objective verification of cancer diagnoses, should yield risk estimates that are both accurate and free of bias. When the familial age-specific hazard ratios (HRs) for prostate cancer diagnosis and mortality were computed, as expected, the HR for prostate cancer diagnosis increased with more family history. Specifically, HRs for prostate cancer were 2.12 (95% CI, 2.05–2.20) with an affected father only, 2.96 (95% CI, 2.80–3.13) with an affected brother only, and 8.51 (95% CI, 6.13–11.80) with a father and two brothers affected. The highest HR, 17.74 (95% CI, 12.26–25.67), was seen in men with three brothers diagnosed with prostate cancer. The HRs were even higher when the affected relative was diagnosed with prostate cancer before age 55 years.

A separate analysis of this Swedish database reported that the cumulative (absolute) risks of prostate cancer among men in families with two or more affected cases were 5% by age 60 years, 15% by age 70 years, and 30% by age 80 years, compared with 0.45%, 3%, and 10%, respectively, by the same ages in the general population. The risks were even higher when the affected father was diagnosed before age 70 years.[24] The corresponding familial population attributable fractions (PAFs) were 8.9%, 1.8%, and 1.0% for the same three age groups, respectively, yielding a total PAF of 11.6% (i.e., approximately 11.6% of all prostate cancers in Sweden can be accounted for on the basis of familial history of the disease).

The risk of prostate cancer may also increase in men who have a family history of breast cancer. Approximately 9.6% of the Iowa cohort had a family history of breast and/or ovarian cancer in a mother or sister at baseline, and this was positively associated with prostate cancer risk (age-adjusted RR, 1.7; 95% CI, 1.0–3.0; multivariate RR, 1.7; 95% CI, 0.9–3.2). Men with a family history of both prostate and breast/ovarian cancer were also at increased risk of prostate cancer (RR, 5.8; 95% CI, 2.4–14.0).[19] Other studies, however, did not find an association between family history of female breast cancer and risk of prostate cancer.[19,25] A family history of prostate cancer also increases the risk of breast cancer among female relatives.[26] The association between prostate cancer and breast cancer in the same family may be explained, in part, by the increased risk of prostate cancer among men with BRCA1/BRCA2 mutations in the setting of hereditary breast/ovarian cancer or early-onset prostate cancer.[27-30] (Refer to the BRCA1 and BRCA2 section of this summary for more information.)

Prostate cancer clusters with particular intensity in some families. Highly penetrant genetic variants are thought to be associated with prostate cancer risk in these families. (Refer to the Linkage Analyses section of this summary for more information.) Members of such families may benefit from genetic counseling. Emerging recommendations and guidelines for genetic counseling referrals are based on prostate cancer age at diagnosis and specific family cancer history patterns.[31,32] Individuals meeting the following criteria may warrant referral for genetic consultation:[31-34]

  • Multiple affected FDRs with prostate cancer.
  • Early-onset prostate cancer (age ≤55 years).
  • Prostate cancer with a family history of other cancers (e.g., breast, ovarian, pancreatic).

Family history has been shown to be a risk factor for men of different races and ethnicities. In a population-based case-control study of prostate cancer among African Americans, whites, and Asian Americans in the United States (Los Angeles, San Francisco, and Hawaii) and Canada (Vancouver and Toronto),[35] 5% of controls and 13% of all cases reported a father, brother, or son with prostate cancer. These prevalence estimates were somewhat lower among Asian Americans than among African Americans or whites. A positive family history was associated with a twofold to threefold increase in RR in each of the three ethnic groups. The overall odds ratio associated with a family history of prostate cancer was 2.5 (95% CI, 1.9–3.3) with adjustment for age and ethnicity.[35]

Other potential modifiers of prostate cancer risk

Endogenous hormones, including both androgens and estrogens, likely influence prostate carcinogenesis. It has been widely reported that eunuchs and other individuals with castrate levels of testosterone prior to puberty do not develop prostate cancer.[36] Some investigators have considered the potential role of genetic variation in androgen biosynthesis and metabolism in prostate cancer risk,[37] including the potential role of the androgen receptor (AR) CAG repeat length in exon 1. This modulates AR activity, which may influence prostate cancer risk.[38] For example, a meta-analysis reported that AR CAG repeat length greater than or equal to 20 repeats conferred a protective effect for prostate cancer in subsets of men.[39]

Some dietary risk factors may be important modulators of prostate cancer risk; these include fat and/or meat consumption,[40] lycopene,[41,42] and dairy products/calcium/vitamin D.[43] Phytochemicals are plant-derived nonnutritive compounds, and it has been proposed that dietary phytoestrogens may play a role in prostate cancer prevention.[44] For example, Southeast Asian men typically consume soy products that contain a significant amount of phytoestrogens; this diet may contribute to the low risk of prostate cancer in the Asian population. There is little evidence that alcohol consumption is associated with the risk of developing prostate cancer; however, data suggest that smoking increases the risk of fatal prostate cancer.[45] Several studies have suggested that vasectomy increases the risk of prostate cancer,[46] but other studies have not confirmed this observation.[47] Obesity has also been associated with increased risk of advanced stage at diagnosis, prostate cancer metastases, and prostate cancer–specific death.[48,49]

Other nutrients have been studied for their potential influence on prostate cancer risk. The effect of selenium and vitamin E in preventing prostate cancer was studied in the Selenium and Vitamin E Cancer Prevention Trial (SELECT). This randomized placebo-controlled trial of selenium and vitamin E among 35,533 healthy men found no evidence of a reduction in prostate cancer risk,[50] although a statistically significant increase (HR, 1.17; 99% CI, 1.004–1.36; P = .008) in prostate cancer with vitamin E supplementation alone was observed.[51] The absolute increased risk associated with vitamin E supplementation compared to placebo after more than 7 years of follow-up was 1.6 per 1,000 person years.

(Refer to the PDQ summary on Prevention of Prostate Cancer for more information about risk factors for prostate cancer in the general population.)

Multiple Primaries

The Surveillance, Epidemiology and End Result Cancer Registries has assessed the risk of developing a second primary cancer in 292,029 men diagnosed with prostate cancer between 1973 and 2000. Excluding subsequent prostate cancer and adjusting for the risk of death from other causes, the cumulative incidence of a second primary cancer among all patients was 15.2% at 25 years (95% CI, 5.01–5.4). There was a significant risk of new malignancies (all cancers combined) among men diagnosed prior to age 50 years, no excess or deficit in cancer risk in men aged 50 to 59 years, and a deficit in cancer risk in all older age groups. The authors suggested that this deficit may be attributable to decreased cancer surveillance in an elderly population. Excess risks of second primary cancers included cancers of the small intestine, soft tissue, bladder, thyroid, and thymus, and melanoma. Prostate cancer diagnosed in patients aged 50 years or younger was associated with an excess risk of pancreatic cancer.[52]

The underlying etiology of developing a second primary cancer after prostate cancer may be related to various factors. Some of the observed excess risks could be associated with prior radiation therapy. Radiation therapy as the initial treatment for prostate cancer was found to increase the risk of bladder and rectal cancers and cancer of the soft tissues. More than 50% of the small intestine tumors were carcinoid malignancies, suggesting possible hormonal influences. The excess of pancreatic cancer may be due to mutations in BRCA2, which predisposes to both. The risk of melanoma was most pronounced in the first year of follow-up after diagnosis, raising the possibility that this is the result of increased screening and surveillance.[52]

One Swedish study using the nationwide Swedish Family Cancer Database assessed the role of family history in the risk of a second primary cancer after prostate cancer. Of 18,207 men with prostate cancer, 560 developed a second primary malignancy. Of those, the RR was increased for colorectal, kidney, bladder, and squamous cell skin cancers. Having a paternal family history of prostate cancer was associated with an increased risk of bladder cancer, myeloma, and squamous cell skin cancer. Among prostate cancer probands, those with a family history of colorectal cancer, bladder cancer, or chronic lymphoid leukemia were at increased risk of that specific cancer as a second primary cancer.[53]

Risk of Other Cancers in Multiple-Case Families

Several reports have suggested an elevated risk of various other cancers among relatives within multiple-case prostate cancer families, but none of these associations have been established definitively.[54-56]

In a population-based Finnish study of 202 multiple-case prostate cancer families, no excess risk of all cancers combined (other than prostate cancer) was detected in 5,523 family members. Female family members had a marginal excess of gastric cancer (standardized incidence ratio [SIR], 1.9; 95% CI, 1.0–3.2). No difference in familial cancer risk was observed when families affected by clinically aggressive prostate cancers were compared with those having nonaggressive prostate cancer. These data suggest that familial prostate cancer is a cancer site–specific disorder.[57]

Inheritance of Prostate Cancer Risk

Many types of epidemiologic studies (case-control, cohort, twin, family) strongly suggest that prostate cancer susceptibility genes exist in the population. An analysis of monozygotic and dizygotic twin pairs in Scandinavia concluded that 42% (95% CI, 29–50) of prostate cancer risk may be accounted for by heritable factors.[58] This is in agreement with a previous U.S. study that showed a concordance of 7.1% between dizygotic twin pairs and a 27% concordance between monozygotic twin pairs.[59] The first segregation analysis was performed in 1992 using families from 740 consecutive probands who had radical prostatectomies between 1982 and 1989. The study results suggested that familial clustering of disease among men with early-onset prostate cancer was best explained by the presence of a rare (frequency of 0.003) autosomal dominant, highly penetrant allele(s).[12] Hereditary prostate cancer susceptibility genes were predicted to account for almost half of early-onset disease (age 55 years or younger). In addition, early-onset disease has been further supported to have a strong genetic component from the study of common variants associated with disease onset before age 55 years.[60]

Subsequent segregation analyses generally agreed with the conclusions but differed in the details regarding frequency, penetrance, and mode of inheritance.[61-63] A study of 4,288 men who underwent radical prostatectomy between 1966 and 1995 found that the best fitting genetic model of inheritance was the presence of a rare, autosomal dominant susceptibility gene (frequency of 0.06). In this study, the lifetime risk in carriers was estimated to be 89% by age 85 years and 3.9% for noncarriers.[59] This study also suggested the presence of genetic heterogeneity, as the model did not reliably predict prostate cancer risk in FDRs of probands who were diagnosed at age 70 years or older. More recent segregation analyses have concluded that there are multiple genes associated with prostate cancer [64-67] in a pattern similar to other adult-onset hereditary cancer syndromes, such as those involving the breast, ovary, colorectum, kidney, and melanoma. In addition, a segregation analysis of 1,546 families from Finland found evidence for Mendelian recessive inheritance. Results showed that individuals carrying the risk allele were diagnosed with prostate cancer at younger ages (<66 years) than noncarriers. This is the first segregation analysis to show a recessive mode of inheritance.[68]

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Identifying Genes and Inherited Variants Associated With Prostate Cancer Risk

Various research methods have been employed to uncover the landscape of genetic variation associated with prostate cancer. Specific methodologies inform of unique phenotypes or inheritance patterns. The sections below describe prostate cancer research utilizing various methods to highlight their role in uncovering the genetic basis of prostate cancer. In an effort to identify disease susceptibility genes, linkage studies are typically performed on high-risk extended families in which multiple cases of a particular disease have occurred. Typically, gene mutations identified through linkage analyses are rare in the population, highly penetrant in families, and have large effect sizes. The clinical role of mutations that are identified in linkage studies is a clearer one, establishing precedent for genetic testing for cancer with genes such as BRCA1 and BRCA2. (Refer to the BRCA1 and BRCA2 section in the Genes With Potential Clinical Relevance in Prostate Cancer Risk section of this summary for more information about these genes.) Genome-wide association studies (GWAS) are another methodology used to identify candidate loci associated with prostate cancer. Genetic variants identified from GWAS typically are common in the population and have modest effect sizes for prostate cancer risk. The clinical role of markers identified from GWAS is an active area of investigation. Case-control studies are useful in validating the findings of linkage studies and GWAS as well as for studying candidate gene alterations for association with prostate cancer risk, although the clinical role of findings from case-control studies needs to be further defined.

Linkage Analyses

Introduction to linkage analyses

The recognition that prostate cancer clusters within families has led many investigators to collect multiple-case families with the goal of localizing prostate cancer susceptibility genes through linkage studies.

Linkage studies are typically performed on high-risk kindreds in whom multiple cases of a particular disease have occurred in an effort to identify disease susceptibility genes. Linkage analysis statistically compares the genotypes between affected and unaffected individuals and looks for evidence that known genetic markers are inherited along with the disease trait. If such evidence is found (linkage), it provides statistical data that the chromosomal region near the marker also harbors a disease susceptibility gene. Once a genomic region of interest has been identified through linkage analysis, additional studies are required to prove that there truly is a susceptibility gene at that position. Linkage analysis is affected by the following:

  • Family size and having a sufficient number of family members who volunteer to contribute DNA.
  • The number of disease cases in each family.
  • Factors related to age at disease onset (e.g., utilization of screening).
  • Gender differences in disease risk (not relevant in prostate cancer but remains relevant in linkage analysis for other conditions).
  • Heterogeneity of disease in cases (e.g., aggressive vs. nonaggressive phenotype).
  • The accuracy of family history information.

Furthermore, because a standard definition of hereditary prostate cancer has not been accepted, prostate cancer linkage studies have not used consistent criteria for enrollment.[1] One criterion that has been proposed is the Hopkins Criteria, which provides a working definition of hereditary prostate cancer families.[2] Using the Hopkins Criteria, kindreds with prostate cancer need to fulfill only one of following criteria to be considered to have hereditary prostate cancer:

  1. Three or more affected first-degree relatives (father, brother, son).
  2. Affected relatives in three successive generations of either maternal or paternal lineages.
  3. At least two relatives affected at age 55 years or younger.

Using these criteria, surgical series have reported that approximately 3% to 5% of men will be from a family with hereditary prostate cancer.[2,3]

An additional issue in linkage studies is the high background rate of sporadic prostate cancer in the context of family studies. Because a man’s lifetime risk of prostate cancer is one in seven,[4] it is possible that families under study have men with both inherited and sporadic prostate cancer. Thus, men who do not inherit the prostate cancer susceptibility gene that is segregating in their family may still develop prostate cancer. Currently there are no clinical or pathological features of prostate cancer that will allow differentiation between inherited and sporadic forms of the disease. Similarly, there are limited data regarding the clinical phenotype or natural history of prostate cancer associated with specific candidate loci. Measurement of the serum prostate-specific antigen (PSA) has been used inconsistently in evaluating families used in linkage analysis studies of prostate cancer. In linkage studies, the definition of an affected man can be biased by the use of serum PSA screening as the rates of prostate cancer in families will differ between screened and unscreened families.

One way to address inconsistencies between linkage studies is to require inclusion criteria that define clinically significant disease (e.g., Gleason score ≥7, PSA ≥20 ng/mL) in an affected man.[5-7] This approach attempts to define a homogeneous set of cases/families to increase the likelihood of identifying a linkage signal. It also prevents the inclusion of cases that may be considered clinically insignificant that were identified by screening in families.

Investigators have also incorporated clinical parameters into linkage analyses with the goal of identifying genes that may influence disease severity.[8,9] This type of approach, however, has not yet led to the identification of consistent linkage signals across datasets.[10,11]

Susceptibility loci identified in linkage analyses

Table 2 summarizes the proposed prostate cancer susceptibility loci identified in families with multiple prostate cancer–affected individuals. Conflicting evidence exists regarding the linkage to some of the loci described above. Data on the proposed phenotype associated with each locus are also limited, and the strength of repeated studies is needed to firmly establish these associations. Evidence suggests that many of these prostate cancer loci account for disease in a small subset of families, which is consistent with the concept that prostate cancer exhibits locus heterogeneity.

Table 2. Proposed Prostate Cancer Susceptibility Loci

GeneLocationCandidate GeneClinical TestingProposed PhenotypeComments
HPC1 (OMIM)/RNASEL (OMIM) [12-34]1q25RNASELNot availableYounger age at prostate cancer diagnosis (<65 y)Evidence of linkage is strongest in families with at least five affected persons, young age at diagnosis, and male-to-male transmission.
Higher tumor grade (Gleason score)
More advanced stage at diagnosisRNASEL mutations have been identified in a few 1q-linked families.
PCAP (OMIM) [1,9,16,23,35-44]1q42.2–43NoneNot availableYounger age at prostate cancer diagnosis (<65 y) and more aggressive diseaseEvidence of linkage is strongest in European families.
HPCX (OMIM) [33,39,45-51]Xq27–28NoneNot availableUnknownMay explain observation that an unaffected man with an affected brother has a higher risk than an unaffected man with an affected father.
CAPB (OMIM) [37,52-54]1p36NoneNot availableYounger age at prostate cancer diagnosis (<65 y)Strongest evidence of linkage was initially described in families with both prostate and brain cancer; follow-up studies indicate that this locus may be associated specifically with early-onset prostate cancer but not necessarily with brain cancer.
One or more cases of brain cancer
HPC20 (OMIM) [39,55-58]20q13NoneNot availableLater age at prostate cancer diagnosis Evidence of linkage is strongest in families with late age at diagnosis, fewer affected family members, and no male-to-male transmission.
No male-to-male transmission
8p [23,40,59-67]8p21–23MSR1Not availableUnknownIn a genomic region commonly deleted in prostate cancer.
8q [44,68-85,85-87]8q24NoneNot availableMore aggressive diseaseData in some reports suggest that the population-attributable risk may be higher for African American men than for men of European origin.
Other genetic loci discovered by linkage analysis

Genome-wide linkage studies of families with prostate cancer have identified several other loci that may harbor prostate cancer susceptibility genes, emphasizing the underlying complexity and genetic heterogeneity of this cancer. The following chromosomal regions have been found to be associated with prostate cancer in more than one study or clinical cohort with a statistically significant (≥2) logarithm of the odds (LOD) score, heterogeneity LOD (HLOD) score, or summary LOD score:

The chromosomal region 19q has also been found to be associated with prostate cancer, although specific LOD scores have not been described.[8,11,95]

Linkage analyses in various familial phenotypes

Linkage studies have also been performed in specific populations or with specific clinical parameters to identify population-specific susceptibility genes or genes influencing disease phenotypes.

Linkage analysis in African American families

The African American Hereditary Prostate Cancer study conducted a genome-wide linkage study of 77 families with four or more affected men. Multipoint HLOD scores of 1.3 to less than 2.0 were observed using markers that map to 11q22, 17p11, and Xq21. Analysis of the 16 families with more than six men with prostate cancer provided evidence for two additional loci: 2p21 (multipoint HLOD score = 1.08) and 22q12 (multipoint HLOD score = 0.91).[92,99] A smaller linkage study that included 15 African American hereditary prostate cancer families from the southeastern and southcentral Louisiana region identified suggestive linkage for prostate cancer at 2p16 (HLOD = 1.97) and 12q24 (HLOD = 2.21) using a 6,000 single nucleotide polymorphism (SNP) platform.[111] Further study including a larger number of African American families is needed to confirm these findings.

Linkage analysis in families with aggressive prostate cancer

In an effort to identify loci contributing to prostate cancer aggressiveness, linkage analysis was performed in families with one or more of the following: Gleason grade 7 or higher, PSA of 20 ng/mL or higher, regional or distant cancer stage at diagnosis, or death from metastatic prostate cancer before age 65 years. One hundred twenty-three families with two or more affected family members with aggressive prostate cancer were studied. Suggestive linkage was found at chromosome 22q11 (HLOD score = 2.18) and 22q12.3-q13.1 (HLOD score = 1.90).[5] These findings suggest that using a clinically defined phenotype may facilitate finding prostate cancer susceptibility genes. A fine-mapping study of 14 extended high-risk prostate cancer families has subsequently narrowed the genomic region of interest to an 880-kb region at 22q12.3.[107] An analysis of high-risk pedigrees from Utah provides an overview of this strategy.[112] A linkage analysis utilizing a higher resolution marker set of 6,000 SNPs was performed among 348 families from the International Consortium for Prostate Cancer Genetics with aggressive prostate cancer.[44] Aggressive disease was defined as Gleason score 7 or higher, invasion into seminal vesicles or extracapsular extension, pretreatment PSA level of 20 ng/mL or higher, or death from prostate cancer. The region with strongest evidence of linkage among aggressive prostate cancer families was 8q24 with LOD scores of 3.09–3.17. Additional regions of linkage included with LOD scores of 2 or higher included 1q43, 2q35, and 12q24.31. No candidate genes have been identified.

Linkage analysis in families with multiple cancers

In light of the multiple prostate cancer susceptibility loci and disease heterogeneity, another approach has been to stratify families based on other cancers, given that many cancer susceptibility genes are pleiotropic.[113] A genome-wide linkage study was conducted to identify a susceptibility locus that may account for both prostate cancer and kidney cancer in families. Analysis of 15 families with evidence of hereditary prostate cancer and one or more cases of kidney cancer (pathologically confirmed) in a man with prostate cancer or in a first-degree relative of a man with prostate cancer revealed suggestive linkage with markers that mapped to an 8 cM region of chromosome 11p11.2-q12.2.[114] This observation awaits confirmation. Another genome-wide linkage study was conducted in 96 hereditary prostate cancer families with one or more first-degree relatives with colon cancer. Evidence for linkage in all families was found in several regions, including 11q25, 15q14, and 18q21. In families with two or more cases of colon cancer, linkage was also observed at 1q31, 11q14, and 15q11-14.[113]

Summary of prostate cancer linkage studies

Linkage to chromosome 17q21-22 and subsequent fine-mapping and exome sequencing have identified recurrent mutations in the HOXB13 gene to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. The clinical utility of testing for HOXB13 mutations has not yet been defined. Furthermore, many linkage studies have mapped several prostate cancer susceptibility loci (Table 2), although the genetic alterations contributing to hereditary prostate cancer from these loci have not been consistently reproduced. With the evolution of high-throughput sequencing technologies, there will likely be additional highly penetrant genetic mutations identified to account for subsets of hereditary prostate cancer families.

Case-Control Studies

A case-control study involves evaluating factors of interest for association to a condition. The design involves investigation of cases with a condition of interest, such as a specific disease or gene mutation, compared with a control sample without that condition, but often with other similar characteristics (i.e., age, gender, and ethnicity). Limitations of case-control design with regard to identifying genetic factors include the following:[115,116]

  • Stratification of the population being studied. (Unknown population based genetic differences between cases and controls that could result in false positive associations.)[117]
  • Genetic heterogeneity. (Different alleles or loci that can result in a similar phenotype.)
  • Limitations of self-identified race or ethnicity and unknown confounding variables.

Additionally, identified associations may not always be valid, but they could represent a random association and, therefore, warrant validation studies.[115,116]

Genes interrogated in case-control studies

Androgen receptor gene

Androgen receptor (AR) gene variants have been examined in relation to both prostate cancer risk and disease progression. The AR is expressed during all stages of prostate carcinogenesis.[118] One study demonstrated that men with hereditary prostate cancer who underwent radical prostatectomy had a higher percentage of prostate cancer cells exhibiting expression of the AR and a lower percentage of cancer cells expressing estrogen receptor alpha than did men with sporadic prostate cancer. The authors suggest that a specific pattern of hormone receptor expression may be associated with hereditary predisposition to prostate cancer.[119]

Altered activity of the AR caused by inherited variants of the AR gene may influence risk of prostate cancer. The length of the polymorphic trinucleotide CAG and GGN microsatellite repeats in exon 1 of the AR gene (located on the X chromosome) have been associated with the risk of prostate cancer.[120,121] Some studies have suggested an inverse association between CAG repeat length and prostate cancer risk, and a direct association between GGN repeat length and risk of prostate cancer; however, the evidence is inconsistent.[118,120-130] A meta-analysis of 19 case-control studies demonstrated a statistically significant association between both short CAG length (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.1–1.3) and short GGN length (OR, 1.3; 95% CI, 1.1–1.6) and prostate cancer; however, the absolute difference in number of repeats between cases and controls is less than one, leading the investigators to question whether these small, statistically significant differences are biologically meaningful.[131] Subsequently, the large multiethnic cohort study of 2,036 incident prostate cancer cases and 2,160 ethnically matched controls failed to confirm a statistically significant association (OR, 1.02; P = .11) between CAG repeat size and prostate cancer.[132] A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between AR alleles, with more than 22 CAG repeats and prostate cancer (OR, 1.35; 95% CI, 1.08–1.69; P = .03).[133]

An analysis of AR gene CAG and CGN repeat length polymorphisms targeted African American men from the Flint Men’s Health Study in an effort to identify a genetic modifier that might help explain the increased risk of prostate cancer in black versus white males in the United States.[134] This population-based study of 131 African American prostate cancer patients and 340 screened-negative African American controls showed no evidence of an association between shorter AR repeat length and prostate cancer risk. These results, together with data from three prior, smaller studies,[132,135,136] indicate that short AR repeat variants do not contribute significantly to the risk of prostate cancer in African American men.

Germline mutations in the AR gene (located on the X chromosome) have been rarely reported. The R726L mutation has been identified as a possible contributor to about 2% of both sporadic and familial prostate cancer in Finland.[137] This mutation, which alters the transactivational specificity of the AR protein, was found in 8 of 418 (1.91%) consecutive sporadic prostate cancer cases, 2 of 106 (1.89%) familial cases, and 3 of 900 (0.33%) normal blood donors, yielding a significantly increased prostate cancer OR of 5.8 for both case groups. A subsequent Finnish study of 38 early-onset prostate cancer cases and 36 multiple-case prostate cancer families with no evidence of male-to-male transmission revealed one additional R726L mutation in one of the familial cases and no new germline mutations in the AR gene.[138] These investigators concluded that germline AR mutations explain only a small fraction of familial and early-onset cases in Finland.

A study of genomic DNA from 60 multiple-case African American (n = 30) and white (n = 30) families identified a novel missense germline AR mutation, T559S, in three affected members of a black sibship and none in the white families. No functional data were presented to indicate that this mutation was clearly deleterious. This was reported as a suggestive finding, in need of additional data.[139]

Steroid 5-alpha-reductase 2 gene (SRD5A2)

Molecular epidemiology studies have also examined genetic polymorphisms of the steroid 5-alpha-reductase 2 gene, which is also involved in the androgen metabolism cascade. Two isozymes of 5-alpha-reductase exist. The gene that codes for 5-alpha-reductase type II (SRD5A2) is located on chromosome 2. It is expressed in the prostate, where testosterone is converted irreversibly to dihydrotestosterone (DHT) by 5-alpha-reductase type II.[140] Evidence suggests that 5-alpha-reductase type II activity is reduced in populations at lower risk of prostate cancer, including Chinese and Japanese men.[141,142]

A polymorphism in the untranslated region of the SRD5A2 gene may also be associated with prostate cancer risk.[143] Ten alleles fall into three families that differ in the number of TA dinucleotide repeats.[140,144] Although no clinical significance for these polymorphisms has yet been determined, some TA repeat alleles may promote an elevation of enzyme activity, which may in turn increase the level of DHT in the prostate.[118,140] A subsequent meta-analysis failed to detect a statistically significant association between prostate cancer risk and the TA repeat polymorphism, although a relationship could not be definitively excluded.[145] This meta-analysis also examined the potential roles of two coding variants: A49T and V89L. An association with V89L was excluded, and the role for A49T was found to have at most a modest effect on prostate cancer susceptibility. Bias or chance could account for the latter observation. A study of 1,461 Swedish men with prostate cancer and 796 control men reported an association between two variants in SRD5A2 and prostate cancer risk (OR, 1.45; 95% CI, 1.01–2.08; OR, 1.49; 95% CI, 1.03–2.15).[133] Another meta-analysis of 25 case-control studies, including 8,615 cases and 9,089 controls, found no overall association between the V89L polymorphism and prostate cancer risk. In a subgroup analysis, men younger than 65 years (323 cases and 677 controls) who carried the LL genotype had a modest association with prostate cancer (LL vs. VV, OR, 1.70; 95% CI, 1.09–2.66 and LL vs. VV+VL, OR, 1.75; 95% CI, 1.14–2.68).[146] A subsequent systematic review and meta-analysis including 27 nonfamilial case-control studies found no statistically significant association between either the V89L or A49T polymorphisms and prostate cancer risk.[147]

Polymorphisms in several genes involved in the biosynthesis, activation, metabolism, and degradation of androgens (CYP17, CYP3A4, CYP19A1, and SRD5A2) and the stimulation of mitogenic and antiapoptotic activities (IGF-1 and IGFBP-3) of normal prostate cells were examined for association with prostate cancer in 131 African American cases and 342 controls. While allele frequencies did not differ between cases and controls regarding three SNPs in the CYP17 gene (rs6163, rs6162, and rs743572), heterozygous genotypes of these SNPs were found to be associated with a reduced risk (OR, 0.56; 95% CI, 0.35–0.88; OR, 0.57; 95% CI, 0.36–0.90; OR, 0.55; 95% CI, 0.35–0.88, respectively). Evidence suggestive of an association between SNP rs5742657 in intron 2 of IGF-1 was also found (OR, 1.57; 95% CI, 0.94–2.63).[148] Additional studies are needed to confirm these findings.

Estrogen receptor-beta gene

Other investigators have explored the potential contribution of the variation in genes involved in the estrogen pathway. A Swedish population study of 1,415 prostate cancer cases and 801 age-matched controls examined the association of SNPs in the estrogen receptor-beta (ER-beta) gene and prostate cancer. One SNP in the promoter region of ER-beta, rs2987983, was associated with an overall prostate cancer risk of 1.23 and 1.35 for localized disease.[149] This study awaits replication.

E-cadherin gene

Germline mutations in the tumor suppressor gene E-cadherin (also called CDH1) cause a hereditary form of gastric carcinoma. A SNP designated -160→A, located in the promoter region of E-cadherin, has been found to alter the transcriptional activity of this gene.[150] Because somatic mutations in E-cadherin have been implicated in the development of invasive malignancies in a number of different cancers,[151] investigators have searched for evidence that this functionally significant promoter might be a modifier of cancer risk. A meta-analysis of 47 case-control studies in 16 cancer types included ten prostate cancer cohorts (3,570 cases and 3,304 controls). The OR of developing prostate cancer among risk allele carriers was 1.33 (95% CI, 1.11–1.60). However, the authors of the study noted that there are sources of bias in the dataset, stemming mostly from the small sample sizes of individual cohorts.[152] Additional studies are required to determine whether this finding is reproducible and biologically and clinically important.

Toll-like receptor genes

There is a great deal of interest in the possibility that chronic inflammation may represent an important risk factor in prostate carcinogenesis.[153] The family of toll-like receptors has been recognized as a critical component of the intrinsic immune system,[154] one which recognizes ligands from exogenous microbes and a variety of endogenous substrates. This family of genes has been studied most extensively in the context of autoimmune disease, but there also have been a series of studies that have analyzed genetic variants in various members of this pathway as potential prostate cancer risk modifiers.[155-159] The results have been inconsistent, ranging from decreased risk, to null association, to increased risk.

One study was based upon 1,414 incident prostate cancer cases and 1,414 age-matched controls from the American Cancer Society Cancer Prevention Study II Nutrition Cohort.[160] These investigators genotyped 28 SNPs in a region on chromosome 4p14 that includes TLR-10, TLR-1, and TLR-6, three members of the toll-like receptor gene cluster. Two TLR-10 SNPs and four TLR-1 SNPs were associated with significant reductions in prostate cancer risk, ranging from 29% to 38% for the homozygous variant genotype. A more detailed analysis demonstrated these six SNPs were not independent in their effect, but rather represented a single strong association with reduced risk (OR, 0.55; 95% CI, 0.33–0.90). There were no significant differences in this association when covariates such as Gleason score, history of benign prostatic hypertrophy, use of nonsteroidal anti-inflammatory drugs, and body mass index were taken into account. This is the largest study undertaken to date and included the most comprehensive panel of SNPs evaluated in the 4p14 region. While these observations provide a basis for further investigation of the toll-like receptor genes in prostate cancer etiology, inconsistencies with the prior studies and lack of information regarding what the biological basis of these associations might be warrant caution in interpreting the findings.

Other genes and polymorphisms interrogated for risk

SNPs in genes involved in the steroid hormone pathway have previously been studied in sporadic and familial prostate cancer using a sample of individuals with primarily Caucasian ancestry.[161] Another study evaluated 116 tagging SNPs located in 12 genes in the steroid hormone pathway for risk of prostate cancer in 886 cases and 1,566 controls encompassing non-Hispanic white men, Hispanic white men, and African American men.[162] The genes included CYP17, HSD17B3, ESR1, SRD5A2, HSD3B1, HSD3B2, CYP19, CYP1A1, CYP1B1, CYP3A4, CYP27B1, and CYP24A1. Several SNPs in CYP19 were associated with prostate cancer risk in all three populations. Analysis of SNP-SNP interactions involving SNPs in multiple genes revealed a seven-SNP interaction involving HSD17B3, CYP19, and CYP24A1 in Hispanic whites (P = .001). In non-Hispanic whites, an interaction of four SNPs in HSD3B2, HSD17B3, and CYP19 was found (P < .001). In African Americans, SNPs within SRD5A2, HSD17B3, CYP17, CYP27B1, CYP19, and CYP24A1 showed a significant interaction (P = .014). In non-Hispanic whites, a cumulative risk of prostate cancer was observed for men carrying risk alleles at three SNPs in HSD3B2 and CYP19 (OR, 2.20; 95% CI, 1.44–3.38; P = .0003). In Hispanic whites, a cumulative risk of prostate cancer was observed for men carrying risk alleles at two SNPs in CYP19 and CYP24A1 (OR, 4.29; 95% CI, 2.11–8.72; P = .00006). While this study did not evaluate all potentially important SNPs in genes in the steroid hormone pathway, it demonstrates how studies can be performed to evaluate multigenic effects in multiple populations to assess the contribution to prostate cancer risk.

A meta-analysis of the relationship between eight polymorphisms in six genes (MTHFR, MTR, MTHFD1, SLC19A1, SHMT1, and FOLH1) from the folate pathway was conducted by pooling data from eight case-control studies, four GWAS, and a nested case-control study named Prostate Testing for Cancer and Treatment in the United Kingdom. Numbers of tested subjects varied among these polymorphisms, with up to 10,743 cases and 35,821 controls analyzed. The report concluded that known common folate-pathway SNPs do not have significant effects on prostate cancer susceptibility in white men.[163]

Four SNPs in the p53 pathway (three in genes regulating p53 function including MDM2, MDM4, and HAUSP and one in p53) were evaluated for association with aggressive prostate cancer in a hospital-based prostate cancer cohort of men with Caucasian ethnicity (N = 4,073).[164] However, a subsequent meta-analysis of case-control studies that focused on MDM2 (T309G) and prostate cancer risk revealed no association.[165] Therefore, the biologic basis of the various associations identified requires further study.

Table 3 summarizes additional case-control studies that have assessed genes that are potentially associated with prostate cancer susceptibility.

Table 3. Case-Control Studies in Genes With Some Association With Prostate Cancer Risk

GeneLocationStudyCasesControlsProstate Cancer AssociationsComments
AMACR (OMIM)5p13.3Zheng et al. (2002) [166]159 U.S. men with familial prostate cancer and 245 men with sporadic prostate cancer211 men without prostate cancer who are participants in a prostate cancer screening programNot assessedGenotype frequencies that compared familial prostate cancer cases to unaffected controls found four missense variants associated with familial prostate cancer (M9V, G1157D, S291L, and K277E).
Daugherty et al. (2007) [167]1,318 U.S. men aged <55 y with prostate cancer (1,211 non-Hispanic whites and 107 non-Hispanic blacks) unselected for family history1,842 U.S. men without prostate cancer who participated in a prostate cancer screening program (1,433 non-Hispanic whites and 409 non-Hispanic blacks) No association was detected between any of the SNPs (M9V, IVS+169G>T, D175G, S201L, Q239H, IVS4+3803C>G, and K277E) and prostate cancer. Risk of prostate cancer was reduced in men who regularly used ibuprofen who also had specific alleles in four SNPs (M9V, D175G, S201L, and K77E) or a specific six-SNP haplotype (TGTGCG).
Levin et al. (2007) [168]449 U.S. white men with familial prostate cancer from 332 familial and early-onset prostate cancer families394 unaffected brothers of the men with prostate cancerSNP rs3195676 (M9V):
OR, 0.58 (95% CI, 0.38–0.90; P = .01 for a recessive model)
NBS1 (OMIM)8q21Hebbring et al. (2006) [169]1,819 U.S. and European men with familial prostate cancer from 909 families and 1,218 U.S. and European men with sporadic prostate cancer697 controls consisting of a mix of U.S. and European population-based controls and unaffected men from prostate cancer families657del5 was not detected in the control population; therefore, testing for an association was not possible.657del5 had a carrier frequency of 0.22% (2 of 909) for familial prostate cancer and 0.25% (3 of 1,218) for sporadic prostate cancer.
Cybulski et al. (2013) [170]3,750 Polish men with prostate cancer3,956 Polish men with no history of cancer675del5: OR, 2.5 (95% CI, 1.5–4.0; P = .0003) NBS1 mutations were associated with a higher mortality (HR, 1.85) and lower 5-year survival (HR, 2.08).
Prostate cancer diagnosed <60 y: OR, 3.1 (95% CI, 1.5–6.4; P = .003)
Familial prostate cancer: OR, 4.3 (95% CI, 2.0–9.0; P = .0001)
KLF6 (OMIM)10p15Narla et al. (2005) [171]1,253 U.S. men with sporadic prostate cancer and 882 men with familial prostate cancer from 294 unrelated families1,276 men with no cancer historyIVS1-27G>A:
Familial cases: OR, 1.61 (95% CI, 1.20–2.16; P = .01)
Sporadic cases: OR, 1.41 (95% CI, 1.08–2.00; P = .01)
Bar-Shira et al. (2006) [172]402 Israeli men with prostate cancer (251 AJ, 151 non-AJ)300 Israeli women aged 20–45 y (200 AJ, 100 non-AJ)IVS1-27G>A:
AJ only: OR, 0.60 (95% CI, 0.35–1.03; P = .047)
Combined cohort: OR, 0.64 (95% CI, 0.42–0.98; P = .047)
EMSY (OMIM) 11q13.5Nurminen et al. (2011) [173]Initial Screen: 184 Finnish men with familial prostate cancer 923 male blood donors from the Finnish Red Cross with no cancer historyIVS6-43A>G: IVS6-43A>G also associated with increased risk of aggressive prostate cancer (PSA ≥20 or Gleason score ≥7) in cases unselected for family history (OR, 6.5; 95% CI, 1.5–28.4; P = .002).
Validation: 2,113 unselected prostate cancer casesFamilial cases: OR, 7.5 (95% CI, 1.3–45.5; P = .02)
Nurminen et al. (2013) [174]2,716 unselected Finnish men with prostate cancer908 male blood donors from the Finnish Red Cross with no cancer historyrs10899221: OR, 1.29 (95% CI, 1.10-1.52); P = .008
rs72944738: OR, 1.26 (95% CI, 1.04-1.52); P = .03
1,318 Finnish men with prostate cancer who participated in the PSA screening arm of the European Randomized Study of Screening for Prostate Cancer rs10899221: OR, 1.40 (95% CI, 1.16-1.69); P = .002
rs72944738: OR, 1.46 (95% CI, 1.16-1.69); P = .003
CHEK2 (OMIM)22q12.1 Dong et al. (2003) [175]84 prostate cancer tumors; 92 prostate cancer tumors diagnosed in men younger than 59 y; 400 U.S. men with prostate cancer and no prostate cancer family history; 298 men with prostate cancer from 149 families (two men per family)510 U.S. men without prostate cancer with a negative prostate cancer screening exam18 CHEK2 mutations were identified in 4.8% (28 of 578) of prostate cancer patients, 0 of 423 unaffected men, and 9 of 149 prostate cancer families.157T was detected in equal numbers of cases and controls and was therefore reported to likely represent a polymorphism.
Cybulski et al. (2013) [170]3,750 Polish men with prostate cancer3,956 Polish men with no history of cancer Any CHEK2 mutation: OR, 1.9 (95% CI, 1.6–2.2; P < .0001)
Prostate cancer diagnosed <60 y: OR, 2.3 (95% CI, 1.8–3.1; P < .0001)
Familial prostate cancer: OR, 2.7 (95% CI, 2.0–3.7; P < .0001)

AJ = Ashkenazi Jewish; CI = confidence interval; HR = hazard ratio; OMIM = Online Mendelian Inheritance in Man; OR = odds ratio; PSA = prostate-specific antigen; SNP = single nucleotide polymorphism.

Case-control studies assessed site-specific prostate cancer susceptibility in the following genes: EMSY, KLF6, AMACR, NBS1, CHEK2, AR, SRD5A2, ER-beta, E-cadherin, and the toll-like receptor genes. These studies have been complicated by the later-onset nature of the disease and the high background rate of prostate cancer in the general population. In addition, there is likely to be real, extensive locus heterogeneity for hereditary prostate cancer, as suggested by both segregation and linkage studies. In this respect, hereditary prostate cancer resembles a number of the other major adult-onset hereditary cancer syndromes, in which more than one gene can produce the same or very similar clinical phenotype (e.g., hereditary breast/ovarian cancer, Lynch syndrome, hereditary melanoma, and hereditary renal cancer). The clinical validity and utility of genetic testing for any of these genes based solely on evidence for hereditary prostate cancer susceptibility has not been established.

Admixture Mapping

Admixture mapping is a method used to identify genetic variants associated with traits and/or diseases in individuals with mixed ancestry.[176] This approach is most effective when applied to individuals whose admixture was recent and consists of two populations who had previously been separated for thousands of years. The genomes of such individuals are a mosaic, comprised of large blocks from each ancestral locale. The technique takes advantage of a difference in disease incidence in one ancestral group compared with another. Genetic risk loci are presumed to reside in regions enriched for the ancestral group with higher incidence. Successful mapping depends on the availability of population-specific genetic markers associated with ancestry, and on the number of generations since admixture.[177,178]

Admixture mapping is a particularly attractive method for identifying genetic loci associated with increased prostate cancer risk among African Americans. African American men are at higher risk of developing prostate cancer than are men of European ancestry, and the genomes of African American men are mosaics of regions from Africa and regions from Europe. It is therefore hypothesized that inherited variants accounting for the difference in incidence between the two groups must reside in regions enriched for African ancestry. In prostate cancer admixture studies, genetic markers for ancestry were genotyped genome-wide in African American cases and controls in a search for areas enriched for African ancestry in the men with prostate cancer. Admixture studies have identified the following chromosomal regions associated with prostate cancer:

An advantage of this approach is that recent admixtures result in long stretches of linkage disequilibrium (up to hundreds of thousands of base pairs) of one particular ancestry.[180] As a result, fewer markers are needed to search for genetic variants associated with specific diseases, such as prostate cancer, than the number of markers needed for successful GWAS.[177] (Refer to the GWAS section of this summary for more information.)

Genome-wide Association Studies (GWAS)

Overview

  • GWAS can identify inherited genetic variants that influence risk of disease.
  • For complex diseases, such as prostate cancer, risk of developing the disease is the product of multiple genetic and environmental factors; each individual factor contributes relatively little to overall risk.
  • To date, GWAS have discovered approximately 100 common genetic variants associated with prostate cancer risk.
  • Individuals can be genotyped for all known prostate cancer risk markers relatively easily; but, to date, studies have not demonstrated that this information substantially refines risk estimates from commonly used variables, such as family history.
  • The clinical relevance of variants identified from GWAS remains unclear.

Introduction to GWAS

Genome-wide searches have successfully identified susceptibility alleles for many complex diseases,[181] including prostate cancer. This approach can be contrasted with linkage analysis, which searches for genetic risk variants co-segregating within families that have a high prevalence of disease. Linkage analyses are designed to uncover rare, highly penetrant variants that segregate in predictable heritance patterns (e.g., autosomal dominant, autosomal recessive, X-linked, and mitochondrial). GWAS, on the other hand, are best suited to identify multiple, common, low-penetrance genetic polymorphisms. GWAS are conducted under the assumption that the genetic underpinnings of complex phenotypes, such as prostate cancer, are governed by many alleles, each conferring modest risk. Most genetic polymorphisms genotyped in GWAS are common, with minor allele frequencies greater than 1% to 5% within a given ancestral population (e.g., men of European ancestry). GWAS survey all common inherited variants across the genome, searching for alleles that are associated with incidence of a given disease or phenotype.[182,183] The strong correlation between many alleles located close to one another on a given chromosome (called linkage disequilibrium) allows one to “scan” the genome without having to test all tens of millions of known SNPs. GWAS can test approximately 1 million to 5 million SNPs and ascertain almost all common inherited variants in the genome.

In a GWAS, allele frequency is compared for each SNP between cases and controls. Promising signals–in which allele frequencies deviate significantly in case compared to control populations–are validated in replication cohorts. In order to have adequate statistical power to identify variants associated with a phenotype, large numbers of cases and controls, typically thousands of each, are studied. Because 1 million SNPs are typically evaluated in a GWAS, false-positive findings are expected to occur frequently whenstandard statistical thresholds are used. Therefore, stringent statistical rules are used to declare a positive finding, usually using a threshold of P < 1 × 10-7.[184-186]

To date, approximately 100 variants associated with prostate cancer have been identified by well-powered GWAS and validated in independent cohorts (see Table 4).[187] These studies have revealed convincing associations between specific inherited variants and prostate cancer risk. However, the findings should be qualified with a few important considerations:

  1. GWAS reported thus far have been designed to identify relatively common genetic polymorphisms. It is very unlikely that an allele with high frequency in the population by itself contributes substantially to cancer risk. This, coupled with the polygenic nature of prostate tumorigenesis, means that the contribution by any single variant identified by GWAS to date is quite small, generally with an OR for disease risk of less than 1.3. In addition, despite extensive genome-wide interrogation of common polymorphisms in tens of thousands of cases and controls, GWAS findings to date do not account for even half of the genetic component of prostate cancer risk.[188,189]
  2. Variants uncovered by GWAS are not likely to be the ones directly contributing to disease risk. As mentioned above, SNPs exist in linkage disequilibrium blocks and are merely proxies for a set of variants—both known and previously undiscovered—within a given block. The causal allele is located somewhere within that linkage disequilibrium block.
  3. Admixture by groups of different ancestry can confound GWAS findings (i.e., a statistically significant finding could reflect a disproportionate number of subjects in the cases versus controls, rather than a true association with disease). Therefore, GWAS subjects, by design, comprise only one ancestral group. As a result, some populations remain underrepresented in genome-wide analyses.

The implications of these points are discussed in greater detail below. Additional detail can be found elsewhere.[190]

Candidate genes and susceptibility loci identified in GWAS

In 2006, two genome-wide studies seeking associations with prostate cancer risk converged on the same chromosomal locus, 8q24. Using a technique called admixture mapping, a 3.8 megabase (Mb) region emerged as significantly involved with risk in African American men.[69] In another study, linkage analysis of 323 Icelandic prostate cancer cases also revealed an 8q24 risk locus.[68] Detailed genotyping of this region and an association study for prostate cancer risk in three case-control populations in Sweden, Iceland, and the United States revealed specific 8q24 risk markers: a SNP, rs1447295, and a microsatellite polymorphism, allele-8 at marker DG8S737.[68] The population-attributable risk of prostate cancer from these alleles was 8%. The results were replicated in an African American case-control population, and the population attributable risk was 16%.[68] These results were confirmed in several large, independent cohorts.[70-73,80-83,191] Subsequent GWAS independently converged on another risk variant at 8q24, rs6983267.[73-75] Fine mapping, genotyping a large number of variants densely packed within a region of interest in many cases and controls, was performed across 8q24 targeting the variants most significantly associated with prostate cancer risk. Across multiple ethnic populations, three distinct 8q24 risk loci were described: region 1 (containing rs1447295) at 128.54–128.62 Mb, region 2 at 128.14–128.28 Mb, and region 3 (containing rs6983267) at 128.47–128.54 Mb.[75] Variants within each of these three regions independently confer disease risk with ORs ranging from 1.11 to 1.66. In 2009, two separate GWAS uncovered two additional risk regions at 8q24. In all, approximately nine genetic polymorphisms, all independently associated with disease, reside within five distinct 8q24 risk regions.[86,87]

Since the discovery of prostate cancer risk loci at 8q24, other chromosomal risk loci similarly have been identified by multistage GWAS comprised of thousands of cases and controls and validated in independent cohorts. The most convincing associations reported to date for men of European ancestry are included in Table 4. The association between risk and allele status for each variant listed in Table 4 reached genome-wide statistical significance in more than one independent cohort.

Table 4. Prostate Cancer Susceptibility Loci Identified Through GWAS in Men of European Ancestry

SNPChromosomal LocusNearest Known Gene Within 100 kbRegionStudy CitationsORa
rs12185821p21KCNN3Intronic[189]1.06
rs175996291p21GOLPH3LIntronic[192]1.10
rs42457391q32MDM4Exonic/Coding[189]0.91
rs101874242p11GGCXIntergenic[188]1.06–1.19
rs7210482p15EHBP1Intronic[193]1.15
rs14656182p21THADAIntronic[194]1.16–1.20
rs119022362p25GRHL1Intronic[189]1.07
rs9287719NOL10Intergenic[192]1.07
rs12621278 2q31ITGA6Intronic[194]1.32–1.47
rs2292884 2q37MLPHIntronic[195]1.14
rs37715702q37FARP2Intronic[189]1.12
rs26607533p12VGLL3Intergenic[196]1.11–1.48
rs76116943q13SIDT1Intronic [189]0.91
rs109348533q21EEFSECIntronic[197]1.12
rs67639313q23ZBTB38Intronic[195]1.04–1.18
rs109366323q26CLDN11Intergenic[188]1.08–1.28
rs18942924q13 AFMIntronic[189]0.91
rs10009409COX18Intergenic[192]1.09
rs125004264q22PDLIM5Intronic[194]1.14–1.17
rs17021918 Intronic[194]1.12–1.25
rs76796734q24TET2Intergenic[194]1.15–1.37
rs21218755p12FGF10Intronic[188]1.05–1.11
rs22426525p15TERTIntronic[195]1.15–1.39
rs68698415q35BOD1Intergenic[189]1.07
rs130067 6p21 CCHCR1Exonic/Coding[195]1.05–1.20
rs3096702NOTCH4Intergenic[189]1.07
rs2273669ARMC2Intronic[189]1.07
rs115306967HLA-DRB6Intergenic[192]1.08
rs1154571356p22TRIM31Intronic[192]1.08
rs47132666p24NEDD9Intronic[192]1.07
rs19334886q25RSG17Intronic[189]0.89
rs9364554SLC22A3Intronic[196,198]1.15–1.26
rs562325067p12TNS3Intronic[192]1.07
rs104865677p15JAZF1Intronic[198,199]1.12–1.35
rs121551727p21NoneIntergenic[189]1.11
rs64656577q21LMTK2Intronic[196]1.03–1.19
rs29286798p21SLC25A37Intergenic[194]1.16–1.26
rs1512268NKX3-1Intergenic[194]1.13–1.28
rs11135910EBF2Intronic[189]1.11
rs100869088q24NoneIntergenic[87]1.14–1.25
rs7841060Intergenic[86]1.19
rs13254738Intergenic[75]1.11
rs16901979 Intergenic[74,198]1.31–1.66
rs16902094Intergenic[197]1.21
rs445114 Intergenic[197]1.14
rs620861Intergenic[86,87]1.11–1.28
rs6983267 Intergenic[73,75,87,198,199]1.13–1.42
rs7000448 Intergenic[75]1.14
rs1447295Intergenic[68,73,74,198]1.29–1.72
rs7837328Intergenic[198]1.14
rs4242382Intergenic[198]1.39
rs176944939p21CDKN2B-AS1Intronic[192]1.10
rs1099399410q11MSMBIntergenic[196,198]1.15–1.42
rs76934034MARCH8Intronic[192]1.14
rs385069910q24TRIM8Intronic[189]0.91
rs496241610q26CTBP2Intronic[199]1.17–1.20
rs712790011p15THIntergenic[194]1.29–1.40
rs1122856511q13MYEOVIntergenic[197]1.23
rs7931342Intergenic[196]1.19–1.25
rs10896449Intergenic[198,200]1.09–1.20
rs12793759Intergenic[200]1.04–1.18
rs10896438Intergenic[200]1.02–1.12
rs1156881811q22MMP7Intergenic[189]0.91
rs1121477511q23HTR3BIntronic[192]1.08
rs90277412q13KRT8Intergenic[195]1.17
rs10875943TUBA1CIntergenic[188]1.02–1.18
rs80130819RP1-228P16.4Intergeneic[192]1.13
rs127088412q24NoneIntergenic[189]1.07
rs800827014q22FERMT2Intronic[189]0.89
rs714152914q24RAD51BIntergenic[189]1.09
rs8014671TTC9Intronic[192]1.07
rs68423217p13VPS53Intergenic[189]1.10
rs1164974317q12HNF1BIntronic[198,201,202]0.86–1.28
rs4430796Intronic[102,198,201,202]0.87–1.12
rs7405696Intronic[202]1.11
rs4794758Intronic[202]0.88
rs1016990Intronic[202]1.07
rs3094509Intronic[202]1.06
rs1165049417q21ZNF652Intergenic[189]1.15
rs185996217q24NoneIntergenic[102,198]1.17–1.20
rs724199318q23SALL3Intergenic[189]0.92
rs810247619q13PPP1R14AIntergenic[197]1.12
rs2735839KLK3Intergenic[196]1.25–1.72
rs17632542KLK3Intergenic[203]0.62–0.76
rs242734520q13RBBP8NLIntergenic[189]0.94
rs6062509ZGPATIntronic[189]0.89
rs575916722q13BIKIntergenic[194]1.14–1.20
rs5945619Xp11NUDT11Intergenic[196,198]1.19–1.46
rs2807031XAGE3Intronic[192]1.07
rs2405942Xp22SHROOM2Intronic[189]0.88
rs5919432Xq12ARIntergenic[195]1.06–1.14
rs6625711Xq13SLC7AIntergenic[192]1.07
rs4844289NLGN3-BCYRN1Intergenic[192]1.05

GWAS = genome-wide association studies; OR = odds ratio; SNP = single nucleotide polymorphism.

aORs are reported as a range across the various stages of GWAS discovery and validation when available.

GWAS in populations of non-European ancestry

Most prostate cancer GWAS data generated to date have been derived from populations of European descent. This shortcoming is profound, considering that linkage disequilibrium structure, SNP frequencies, and incidence of disease differ across ancestral groups. To provide meaningful genetic data to all patients, well-designed, adequately powered GWAS must be aimed at specific ethnic groups.[204] Most work in this regard has focused on African American, Chinese, and Japanese men. The most convincing associations reported to date for men of non-European ancestry are included in Table 5. The association between risk and allele status for each variant listed in Table 5 reached genome-wide statistical significance in more than one independent cohort.

Table 5. Prostate Cancer Susceptibility Loci Identified Through Genome-wide Association Studies (GWAS) in Men of Non-European Ancestry

SNP Chromosomal LocusNearest Known Gene Within 100 kbRegionStudy Citations ORa
African American Population
rs169019798q24NoneIntergenic[205]1.00–1.57
rs6983267Intergenic[205]0.83–2.43
rs7839365Intergenic[206]1.16–1.18
rs753228Intergenic[206]1.41–1.43
rs4871008Intergenic[206]1.15–1.19
rs1456315Intergenic[206]1.23–1.27
rs10098156Intergenic[206]1.26–1.30
rs6987409Intergenic[206]1.33–1.42
rs13282506Intergenic[206]1.25–1.28
rs7812429Intergenic[206]1.30–1.31
rs4313118Intergenic[206]1.16–1.17
rs1447295Intergenic[69]1.05
DG85737Intergenic[69]1.05
rs721010017q21ZNF652Intronic[207]1.40–1.67
Chinese Population
rs8178269q31.2RAD23B-KLF4Intergenic[208]1.33–1.43
rs10329419q13.4LILRA3Intergenic[208]1.25–1.40
Japanese Population
rs20288982p11GGCXIntronic[209]0.96–1.22
rs133851912p24C2orf43Intronic[210]1.12–1.22
rs20551093p11.2NoneIntergenic[209]1.15–1.33
rs26607533p12.1NoneIntergenic[211]1.42
rs126539465p15NoneIntergenic[210]1.23–1.31
rs19838916p21FOXP4Intronic[210]1.11–1.23
rs339331 6q22RFX6 and GPRC6AIntronic[210]1.18–1.22
rs13254738 8q24NoneIntergenic [211]1.59
rs6983561 Intergenic [211]1.81
rs100090154Intergenic [211]1.41
rs225200410q26NoneIntergenic[209]1.12–1.23
rs193878111q12FAM111AIntergenic[209]1.11–1.25
rs960007913q22NoneIntergenic[210]1.17–1.19
rs443079617q12NoneIntronic[211]1.51

OR = odds ratio; SNP = single nucleotide polymorphism.

aORs are reported as a range across the various stages of GWAS discovery and validation when available.

The African American population is of particular interest because American men with African ancestry are at higher risk of prostate cancer than any other group. In addition, inherited variation at the 8q24 risk locus appears to contribute to differences in African American and European American incidence of disease.[69] A handful of studies have sought to determine whether GWAS findings in men of European ancestry are applicable to men of African ancestry. One study interrogated 28 known prostate cancer risk loci via fine mapping in 3,425 African American cases and 3,290 African American controls.[206] On average, risk allele frequencies were 0.05 greater in African Americans than in European Americans. Of the 37 known risk SNPs analyzed, 18 replicated in the African American population were significantly associated with prostate cancer at P ≤ .05 (the study was underpowered to properly assess nine of the remaining 19 SNPs). For seven risk regions (2p24, 2p15, 3q21, 6q22, 8q21, 11q13, and 19q13), fine mapping identified SNPs in the African American population more strongly associated with risk than the index SNPs reported in the original European-based GWAS. Fine mapping of the 8q24 region revealed four SNPs associated with disease that are substantially more common in African Americans. The SNP most strongly correlated with disease among African Americans (rs6987409) is not strongly correlated with a European risk allele and may account for a portion of increased risk in the African American population. In all, the risk SNPs identified in this study are estimated to represent 11% of total inherited risk.

Some of the risk variants identified in Table 5 have also been found to confer risk in men of European ancestry. These include rs16901979, rs6983267, and rs1447295 at 8q24 in African Americans and rs13254738 in Japanese populations. Additionally, the Japanese rs4430796 at 17q12 and rs2660753 at 3p12 have also been observed in men of European ancestry. However, the vast majority of the variants identified in these studies reveal novel variants that are unique to that specific ethnic population. These results confirm the importance of evaluating SNP associations in different ethnic populations. Considerable effort is still needed to fully annotate genetic risk in these and other populations.

Clinical application of GWAS findings

Because the variants discovered by GWAS are markers of risk, there has been great interest in using genotype as a screening tool to predict the development of prostate cancer. In an attempt to determine the potential clinical value of risk SNP genotype, cases of prostate cancer (n = 2,893) were identified from four cancer registries in Sweden. Controls (n = 1,781) were randomly selected from the Swedish Population Registry and were matched to cases by age and geographic region.[78] Known risk SNPs from 8q24, 17q12, and 17q24.3 were analyzed (rs4430796 at 17q12, rs1859962 at 17q24.3, rs16901979 at 8q24 [region 2], rs6983267 at 8q24 [region 3], and rs1447295 at 8q24 [region 1]). ORs for prostate cancer for men carrying any combination of one, two, three, or four or more genotypes associated with prostate cancer were estimated by comparing them with men carrying none of the associated genotypes using logistic regression analysis. Men who carried one to five risk alleles had an increasing likelihood of having prostate cancer compared with men carrying none of the alleles (P = 6.75 × 10-27). After controlling for age, geographic location, and family history of prostate cancer, men carrying four or more of these alleles had a significant elevation in risk of prostate cancer (OR, 4.47; 95% CI, 2.93–6.80; P = 1.20 × 10-13). When family history was added as a risk factor, men with five or more factors (five SNPs plus family history) had an even stronger risk of prostate cancer (OR, 9.46; 95% CI, 3.62–24.72; P = 1.29 × 10-8). The population-attributable risks (PARs) for these five SNPs were estimated to account for 4% to 21% of prostate cancer cases in Sweden, and the joint PAR for prostate cancer of the five SNPs plus family history was 46%.

A second study assessed prostate cancer risk associated with a family history of prostate cancer in combination with various numbers of 27 risk alleles identified through four prior GWAS. Two case-control populations were studied, the Prostate, Lung, Colon, and Ovarian Cancer Screening Trial (PLCO) in the United States (1,172 cases and 1,157 controls) and the Cancer of the Prostate in Sweden (CAPS) study (2,899 cases and 1,722 controls). The highest risk of prostate cancer from the CAPS population was observed in men with a positive family history and greater than 14 risk alleles (OR, 4.92; 95% CI, 3.64–6.64). Repeating this analysis in the PLCO population revealed similar findings (OR, 3.88; 95% CI, 2.83–5.33).[212]

However, the proportion of men carrying large numbers of the risk alleles was low. While ORs were impressively high for this subset, they do not reflect the utility of genotyping the overall population. Receiver operating characteristic curves were constructed in these studies to measure the sensitivity and specificity of certain risk profiles. The area under the curve (AUC) was 0.61 when age, geographic region, and family history were used to assess risk. When genotype of the five risk SNPs at chromosomes 8 and 17 were introduced, a very modest AUC improvement to 0.63 was detected.[78] The addition of more recently discovered SNPs to the model has not appreciably improved these results.[213] While genotype may inform risk status for the small minority of men carrying multiple risk alleles, testing of the known panel of prostate cancer SNPs is currently of questionable clinical utility.[214]

Another study incorporated 10,501 prostate cancer cases and 10,831 controls from multiple cohorts (including PLCO) and genotyped each individual for 25 prostate cancer risk SNPs. Age and family history data were available for all subjects. Genotype data helped discriminate those who developed prostate cancer from those who did not. However, similar to the series above, discriminative ability was modest and only compelling at the extremes of risk allele distribution in a relatively small subset population; younger subjects (men aged 50 to 59 years) with a family history of disease who were in 90th percentile for risk allele status had an absolute 10-year risk of 6.7% compared with an absolute 10-year risk of 1.6% in men in the 10th percentile for risk allele status.[215]

In July 2012, the Agency for Healthcare Research and Quality (AHRQ) published a report that sought to address the clinical utility of germline genotyping of prostate cancer risk markers discovered by GWAS.[214] Largely on the basis of the evidence from the studies described above, AHRQ concluded that established prostate cancer risk SNPs have “poor discriminative ability” to identify individuals at risk of developing the disease. Similarly, the authors of another study estimated that the contribution of GWAS polymorphisms in determining the risk of developing prostate cancer will be modest, even as meta-analyses or larger studies uncover additional “common” risk alleles (alleles carried by >1%–5% of individuals within the population).[216]

GWAS findings to date account for only a fraction of heritable risk of disease. Research is ongoing to uncover the remaining portion of genetic risk. This includes the discovery of rarer alleles with higher ORs for risk. For example, a consortium led by deCODE genetics in Iceland performed whole-genome sequencing of 2,500 Icelanders and identified approximately 32.5 million variants, including millions of rare variants (carried by <1% of the population). These variants were analyzed in 5,141 prostate cancer cases and 54,444 controls (genotypes were imputed in cases in which they had not been genotyped in previous analyses). In addition to previously reported risk alleles at 8q24 and 17q12, significant associations with prostate cancer were observed for two rare 8q24 SNPs—the minor allele (the G allele) of rs183373024 (OR, 2.69; P = 1.5 × 10−23) and the minor allele (the A allele) of rs188140481 (OR, 2.88; P = 1.5 × 10−22).[217] These results were validated in independent cohorts of European cases and controls. The frequencies of the risk alleles of these two variants in controls ranged from 0.1% to 1.1% and were lowest in southern Europe and highest in northern Europe. These data, in which risk alleles had high ORs compared with previous GWAS, demonstrate that the bulk of inherited risk may reside in rare alleles.

In addition, other genetic polymorphisms, such as copy number variants, are becoming increasingly amenable to testing. As the full picture of inherited prostate cancer risk becomes more complete, it is hoped that germline information will become clinically useful.

GWAS and insight into the mechanism of prostate cancer risk

Notably, almost all reported prostate cancer risk alleles reside in nonprotein coding regions of the genome, and the underlying biological mechanism of disease susceptibility remains unclear. Hypotheses explaining the mechanism of inherited risk include the following:

  • Risk alleles discovered by GWAS are in linkage disequilibrium with exonic variants that directly influence gene products.
  • Risk alleles do in fact reside in areas of transcription, but transcription at these sites has not yet been annotated.
  • Risk alleles reside within regulatory elements and genotype within these areas influence activity of distal genes.[218]

The 8q24 risk locus, which contains multiple prostate cancer risk alleles and risk alleles for other cancers, has been the focus of intense study. c-MYC, a known oncogene, is the closest known gene to the 8q24 risk regions, although it is located hundreds of kb away. Given this significant distance, SNPs within c-MYC are not in linkage disequilibrium with the 8q24 prostate cancer risk variants. One study examined whether 8q24 prostate cancer risk SNPs are in fact located in areas of previously unannotated transcription, and no transcriptional activity was uncovered at the risk loci.[219] Attention turned to the idea of distal gene regulation. Interrogation of the epigenetic landscape at the 8q24 risk loci revealed that the risk variants are located in areas that bear the marks of genetic enhancers, elements that influence gene activity from a distance.[220-222] To identify a prostate cancer risk gene, germline DNA from 280 men undergoing prostatectomy for prostate cancer was genotyped for all known 8q24 risk SNPs. Genotypes were tested for association with the normal prostate and prostate tumor RNA expression levels of genes located within one Mb of the risk SNPs. No association was detected between expression of any of the genes, including c-MYC, and risk allele status in either normal epithelium or tumor tissue. Another study, using normal prostate tissue from 59 patients, detected an association between an 8q24 risk allele and the gene PVT1, downstream from c-MYC.[223] Nonetheless, c-MYC, with its substantial involvement in many cancers, remains a prime candidate. A series of experiments in prostate cancer cell lines demonstrated that chromatin is configured in such a way that the 8q24 risk variants lie in close proximity to c-MYC, even though they are quite distant in linear space. These data implicate c-MYC despite the absence of expression data.[221,223] Further work at 8q24 and similar analyses at other prostate cancer risk loci are ongoing.

Additional insights are emerging regarding the potential interaction between SNPs identified from GWAS and prostate cancer susceptibility gene regulation. One study found that a SNP at 6q22 lies within a binding region for HOXB13. Through multiple functional approaches, the T allele of this SNP (rs339331) was found to enhance binding of HOXB13, leading to allele-specific upregulation of RFX6, which correlates with prostate cancer progression and severity.[224] Thus, this study supports the hypothesis that risk alleles identified from GWAS may play a role in regulating or modifying gene expression and therefore impact prostate cancer risk.

Modified approaches to GWAS

A 2012 study used a novel approach to identify polymorphisms associated with risk.[225] On the basis of the well-established principle that the AR plays a prominent role in prostate tumorigenesis, the investigators targeted SNPs that reside at sites where the AR binds to DNA. They leveraged data from previous studies that mapped thousands of AR binding sites genome-wide in prostate cancer cell lines to select SNPs to genotype in the Johns Hopkins Hospital cohort of 1,964 cases and 3,172 controls and the Cancer Genetic Markers of Susceptibility cohort of 1,172 cases and 1,157 controls. This modified GWAS revealed a SNP (rs4919743) located at the KRT8 locus at 12q13.13—a locus previously implicated in cancer development—associated with prostate cancer risk, with an OR of 1.22 (95% CI, 1.13–1.32). The study is notable for its use of a reasonable hypothesis and prior data to guide a genome-wide search for risk variants.

Conclusions

Although the statistical evidence for an association between genetic variation at these loci and prostate cancer risk is overwhelming, the clinical relevance of the variants and the mechanism(s) by which they lead to increased risk are unclear and will require further characterization. Additionally, these loci are associated with very modest risk estimates and explain only a fraction of overall inherited risk. Further work will include genome-wide analysis of rarer alleles catalogued via sequencing efforts, such as the 1000 Genomes Project.[226] Disease-associated alleles with frequencies of less than 1% in the population may prove to be more highly penetrant and clinically useful. In addition, further work is needed to describe the landscape of genetic risk in non-European populations. Finally, until the individual and collective influences of genetic risk alleles are evaluated prospectively, their clinical utility will remain difficult to fully assess.

Inherited Variants Associated With Prostate Cancer Aggressiveness

Prostate cancer is clinically heterogeneous. Many cases are indolent and are successfully managed with observation alone. Other cases are quite aggressive and prove deadly. Several variables are used to determine prostate cancer aggressiveness at the time of diagnosis, such as Gleason score and PSA, but these are imperfect. Additional markers are needed, as sound treatment decisions depend on accurate prognostic information. Germline genetic variants are attractive markers since they are present, easily detectable, and static throughout life. Several studies have interrogated inherited variants that may distinguish indolent and aggressive prostate cancer. Several of these studies identified polymorphisms associated with aggressiveness, after adjusting for commonly used clinical variables, and are reviewed in the Table 6.

Findings to date regarding inherited risk of aggressive disease are considered preliminary. Further work is needed to validate findings and assess prospectively.

Like studies of the genetics of prostate cancer risk, initial studies of inherited risk of aggressive prostate cancer focused on polymorphisms in candidate genes. Next, as GWAS revealed prostate cancer risk SNPs, several research teams sought to determine whether certain risk SNPs were also associated with aggressiveness (see table below). There has been great interest in launching more unbiased, genome-wide searches for inherited variants associated with indolent versus aggressive prostate cancer. While GWAS designed explicitly for disease aggressiveness have been initiated, most genome-wide analyses to date have relied on datasets previously generated to evaluate prostate cancer risk. The cases from these case-control cohorts were divided into aggressive and nonaggressive subgroups then compared with each other and/or with the control (nonprostate cancer) subjects. Several associations between germline markers and prostate cancer aggressiveness have been reported. However, there remains no accepted set of germline markers that clearly provides prognostic information beyond that provided by more traditional variables at the time of diagnosis.

Table 6. Inherited Variants Associated With Prostate Cancer Aggressivenessa

Source of Associated Polymorphism VariantPhenotype Controls Associated Allele/Genotype and Strength of AssociationReference
Target gene – CASP8D302HPSA level >50 ng/mL or metastasis or Gleason 8–10 (n = 796)Men without prostate cancer (n = 2,060)H allele: OR, 0.67 (95% CI, 0.54–0.83)[227]
Target gene – CCL21181 A/GBiopsy Gleason >7 (n = 705)Biopsy Gleason ≤7 (n = 3,031)AA genotype: OR, 1.47 (95% CI, 1.08–2.01)[228]
Target gene – MDM2rs2279744 G/TBiopsy Gleason >7 (n = 1,028)Biopsy Gleason ≤7 (n = 645)TT genotype: OR, 1.51 (95% CI, 1.11–2.05)[164]
GWAS risk SNPrs2735839 A/GGleason ≥4+3 or T3b or N+ (n = 1,253)Gleason ≤4+3 and <T3b and N- (n = 4,233) A allele (more aggressive prostate cancer) and G allele (less aggressive prostate cancer): OR, 1.38 (95% CI, 1.21–1.56)[229]
Gleason ≥8 (n = 1,388)Gleason <8 (n = 7,549)A allele (more aggressive prostate cancer) and G allele (less aggressive prostate cancer): OR, 1.07 (95% CI, 0.95–1.19)[230]
Prostate cancer–specific death (n = 580)Nonprostate cancer death or survival at last follow-up (n = 3,365)A allele (more aggressive prostate cancer) and G allele (less aggressive prostate cancer): OR, 1.26 (95% CI, 1.05–1.52)[231]
Gleason ≥8 or PSA >20 ng/mL or Gleason 7 and cT3–cT4 (n = 212 African Americans)Gleason <7 and cT1–cT2 and PSA <10 ng/mL (n = 469 African Americans)G allele: OR, 0.8 (95% CI, 0.6–0.9)[232]
Target gene – LEPRrs1137100 A/GProstate cancer–specific death (n = 501)Nonprostate cancer death or survival at last follow-up (n = 2,374)G allele: HR, 0.82 (95% CI, 0.67–1.00)[233]
Target gene – IL4rs2070874 C/TProstate cancer–specific death (n = 501)Nonprostate cancer death or survival at last follow-up (n = 2,374)T allele: HR, 1.27 (95% CI, 1.04–1.56)[233]
Target gene – CRY1rs10778534 C/TProstate cancer–specific death (n = 501)Nonprostate cancer death or survival at last follow-up (n = 2,374)C allele: HR, 1.23 (95% CI, 1.00–1.51)[233]
Target gene – EMSYrs12277366_GProstate cancer-specific death (n = not reported)Three groups studied for prostate-cancer specific death:OR, 0.72 (95% CI, 0.61–0.84)[174]
– Unselected Finnish men with prostate cancer (n = 2,716)
– Finnish men with prostate cancer who participated in the PSA screening arm of the European Randomized Study of Screening for Prostate Cancer (n = 1,318)
– Controls: male blood donors from the Finnish Red Cross with no cancer history (n = 908)
GWAS risk SNPrs11672691 A/GProstate-cancer–specific death (n = 1,053)Men without prostate cancer (n = 2,060)G allele: HR, 1.18 (95% CI, 1.05–1.34)[234]

CI = confidence interval; GWAS = genome-wide association study; HR = hazard ratio; N- = lymph node–negative; N+ = lymph node–positive; OR = odds ratio; PSA = prostate-specific antigen; SNP = single nucleotide polymorphism.

aAll study populations are of European ancestry except where noted.

In independent retrospective series (see Table 6) the prostate cancer risk allele at rs2735839 (G) was associated with less aggressive disease. This risk allele has also been associated with higher PSA levels.[196,235] A hypothesis explaining the association between the nonrisk allele (A) and more aggressive disease is that those carrying the A allele generally have lower PSA levels and are sent for prostate biopsy less often. They subsequently may be diagnosed later in the natural history of the disease, resulting in poorer outcomes.

To definitively identify the inherited variants associated with prostate cancer aggressiveness, GWAS focusing on prostate cancer subjects with poor disease-related outcomes are needed. Genome-wide surveys for aggressiveness variants have been attempted, although these were underpowered to detect polymorphisms with ORs lower than 2.0.[236,237] As these data are generated and validated, inherited variants may become valuable in accurately determining prostate cancer prognosis and establishing a treatment plan.

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Genes With Potential Clinical Relevance in Prostate Cancer Risk

While genetic testing for prostate cancer is not yet standard clinical practice, research from selected cohorts has reported that prostate cancer risk is elevated in men with mutations in BRCA1, BRCA2, and on a smaller scale, in mismatch repair (MMR) genes. Since clinical genetic testing is available for these genes, information about risk of prostate cancer based on alterations in these genes is included in this section. In addition, mutations in HOXB13 were reported to account for a proportion of hereditary prostate cancer. Although clinical testing is not yet available for HOXB13 alterations, it is expected that this gene will have clinical relevance in the future and therefore it is also included in this section. The genetic alterations described in this section require further study and are not to be used in routine clinical practice at this time.

BRCA1 and BRCA2

Studies of male BRCA1 [1] and BRCA2 mutation carriers demonstrate that these individuals have a higher risk of prostate cancer and other cancers.[2] Prostate cancer in particular has been observed at higher rates in male BRCA2 mutations carriers than in the general population.[3]

BRCA mutation–associated prostate cancer risk

The risk of prostate cancer in BRCA mutation carriers has been studied in various settings.

In an effort to clarify the relationship between BRCA mutations and prostate cancer risk, findings from several case series are summarized in Table 7.

Table 7. Case Series of BRCA Mutations in Prostate Cancer

StudyPopulationProstate Cancer Risk (BRCA1)Prostate Cancer Risk (BRCA2)
BCLC (1999) [4]BCLC family set that included 173 BRCA2 linkage– or mutation–positive families, among which there were 3,728 individuals and 333 cancersa Not assessedOverall: RR, 4.65 (95% CI, 3.48–6.22)
Men <65 y: RR, 7.33 (95% CI, 4.66–11.52)
Thompson et al. (2001) [5]BCLC family set that included 164 BRCA2 mutation–positive families, among which there were 3,728 individuals and 333 cancersaNot assessedOCCR: RR, 0.52 (95% CI, 0.24–1.00)
Thompson et al. (2002) [1]BCLC family set that included 7,106 women and 4,741 men, among which 2,245 were BRCA1 mutation carriers; 1,106 were tested noncarriers, and 8,496 were not tested for mutationsOverall: RR, 1.07 (95% CI, 0.75–1.54) Not assessed
Men younger than 65 y: RR, 1.82 (95% CI, 1.01–3.29)
Mersch et al. (2015) [3]Clinical genetics population at a single institution from 1997–2013. Compared cancer incidence to U.S. Statistics Report by CDC for general population cancer incidence. SIR = 3.809 (95% CI, 0.766–11.13) (Not significant) SIR = 4.89 (95% CI, 1.959–10.075)

BCLC = Breast Cancer Linkage Consortium; CDC = Centers for Disease Control and Prevention; CI = confidence interval; OCCR = Ovarian Cancer Cluster Region; RR = relative risk; SIR = standardized incidence ratio.

aIncludes all cancers except breast, ovarian, and nonmelanoma skin cancers.

Estimates derived from the Breast Cancer Linkage Consortium may be overestimated because these data are generated from a highly select population of families ascertained for significant evidence of risk of breast cancer and ovarian cancer and suitability for linkage analysis. However, a review of the relationship between germline mutations in BRCA2 and prostate cancer risk supports the view that this gene confers a significant increase in risk among male members of hereditary breast and ovarian cancer families but that it likely plays only a small role, if any, in site-specific, multiple-case prostate cancer families.[6] In addition, the clinical validity and utility of BRCA testing solely on the basis of evidence for hereditary prostate cancer susceptibility has not been established.

Prevalence of BRCA founder mutations in men with prostate cancer

Ashkenazi Jewish

Several studies in Israel and in North America have analyzed the frequency of BRCA founder mutations among Ashkenazi Jewish (AJ) men with prostate cancer.[7-9] Two specific BRCA1 mutations (185delAG and 5382insC) and one BRCA2 mutation (6174delT) are common in individuals of AJ ancestry. Carrier frequencies for these mutations in the general Jewish population are 0.9% (95% CI, 0.7–1.1) for the 185delAG mutation, 0.3% (95% confidence interval [CI], 0.2–0.4) for the 5382insC mutation, and 1.3% (95% CI, 1.0–1.5) for the BRCA2 6174delT mutation.[10-13] (Refer to the High-Penetrance Breast and/or Gynecologic Cancer Susceptibility Genes section in the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about BRCA1 and BRCA2 genes.) In these studies, the relative risks were commonly greater than 1, but only a few have been statistically significant. Many of these studies were not sufficiently powered to rule out a lower, but clinically significant, risk of prostate cancer in carriers of Ashkenazi BRCA founder mutations.

In the Washington Ashkenazi Study (WAS), a kin-cohort analytic approach was used to estimate the cumulative risk of prostate cancer among more than 5,000 American AJ male volunteers from the Washington, District of Columbia, area who carried one of the BRCA Ashkenazi founder mutations. The cumulative risk to age 70 years was estimated to be 16% (95% CI, 4–30) among carriers and 3.8% among noncarriers (95% CI, 3.3–4.4).[13] This fourfold increase in prostate cancer risk was equal (in absolute terms) to the cumulative risk of ovarian cancer among female mutation carriers at the same age (16% by age 70 years; 95% CI, 6–28). The risk of prostate cancer in male mutation carriers in the WAS cohort was elevated by age 50 years, was statistically significantly elevated by age 67 years, and increased thereafter with age, suggesting both an overall excess in prostate cancer risk and an earlier age at diagnosis among carriers of Ashkenazi founder mutations. Prostate cancer risk differed depending on the gene, with BRCA1 mutations associated with increasing risk after age 55 to 60 years, reaching 25% by age 70 years and 41% by age 80 years. In contrast, prostate cancer risk associated with the BRCA2 mutation began to rise at later ages, reaching 5% by age 70 years and 36% by age 80 years (numeric values were provided by the author [written communication, April 2005]).

The studies summarized in Table 8 used similar case-control methods to examine the prevalence of Ashkenazi founder mutations among Jewish men with prostate cancer and found an overall positive association between founder mutation status and prostate cancer risk.

Table 8. Case-Control Studies in Ashkenazi Jewish Populations of BRCA1 and BRCA2 and Prostate Cancer Risk

StudyCases / ControlsMutation Freq. BRCA1)Mutation Freq. (BRCA2)Prostate Cancer Risk (BRCA1)Prostate Cancer Risk (BRCA2)Comments
Guisti et al. (2003) [14]Cases: 979 consecutive AJ men from Israel diagnosed with prostate cancer between 1994 and 1995 Cases: 16 (1.7%) Cases: 14 (1.5%) 185delAG: OR, 2.52 (95% CI, 1.05–6.04)OR, 2.02 (95% CI, 0.16–5.72)There was no evidence of unique or specific histopathology findings within the mutation-associated prostate cancers.
Controls: Prevalence of founder mutations compared with age-matched controls >50 years with no history of prostate cancer from the WAS study and the MECC study from IsraelControls: 11 (0.81%)Controls: 10 (0.74%5282insC: OR, 0.22 (95% CI, 0.16–5.72)
Kirchoff et al. (2004) [15]Cases: 251 unselected AJ men treated for prostate cancer between 2000 and 2002 Cases: 5 (2.0%)Cases: 8 (3.2%)OR, 2.20 (95% CI, 0.72–6.70)OR, 4.78 (95% CI, 1.87–12.25)
Controls: 1,472 AJ men with no history of cancerControls: 12 (0.8%)Controls: 16 (1.1%)
Agalliu et al. (2009) [16]Cases: 979 AJ men diagnosed with prostate cancer between 1978 and 2005 (mean and median year of diagnosis: 1996) Cases: 12 (1.2%)Cases: 18 (1.9%)OR, 1.39 (95% CI, 0.60–3.22)OR, 1.92 (95% CI, 0.91–4.07)Gleason score 7–10 prostate cancer was more common in BRCA1 mutation carriers (OR, 2.23; 95% CI, 0.84–5.86) and BRCA2 mutation carriers (OR, 3.18; 95% CI, 1.62–6.24) than in controls.
Controls: 1,251 AJ men with no history of cancerControls: 11 (0.9%)Controls: 12 (1.0%)
Gallagher et al. (2010) [17]Cases: 832 AJ men diagnosed with localized prostate cancer between 1988 and 2007Noncarriers: 806 (96.9%)Noncarriers: 447 (98.5%)OR, 0.38 (95% CI, 0.05–2.75)OR, 3.18 (95% CI, 1.52–6.66)The BRCA1 5382insC founder mutation was not tested in this series, so it is likely that some carriers of this mutation were not identified. Consequently, BRCA1-related risk may be underestimated. Gleason score 7–10 prostate cancer was more common in BRCA2 mutation carriers (85%) than in noncarriers (57%); P = .0002. BRCA1/2 mutation carriers had significantly greater risk of recurrence and prostate cancer–specific death than did noncarriers.
Cases: 6 (0.7%)Cases: 20 (2.4%)
Controls: 454 AJ men with no history of cancerControls: 4 (0.9%)Controls: 3 (0.7%)

AJ = Ashkenazi Jewish; CI = confidence interval; MECC = Molecular Epidemiology of Colorectal Cancer; OR = odds ratio; WAS = Washington Ashkenazi Study.

These studies support the hypothesis that prostate cancer occurs excessively among carriers of AJ founder mutations and suggest that the risk may be greater among men with the BRCA2 founder mutation (6174delT) than among those with one of the BRCA1 founder mutations (185delAG; 5382insC). The magnitude of the BRCA2-associated risks differ somewhat, undoubtedly because of interstudy differences related to participant ascertainment, calendar time differences in diagnosis, and analytic methods. Some data suggest that BRCA-related prostate cancer has a significantly worse prognosis than prostate cancer that occurs among noncarriers.[17]

Other populations

The association between prostate cancer and mutations in BRCA1 and BRCA2 has also been studied in other populations. Table 9 summarizes studies that used case-control methods to examine the prevalence of BRCA mutations among men with prostate cancer from other varied populations.

Table 9. Case-Control Studies in Varied Populations of BRCA1 and BRCA2 and Prostate Cancer Risk

StudyCases / ControlsMutation Freq. (BRCA1)Mutation Freq. (BRCA2)Prostate Cancer Risk (BRCA1)Prostate Cancer Risk (BRCA2)Comments
Johannesdottir et al. (1996) [18]Cases: 75 Icelandic men diagnosed with prostate cancer <65 y, between 1983 and 1992, with available archival tissue blocks Not assessedCases: 999del5 (2.7%) Not assessed999del5: RR, 2.5 (95% CI, 0.49–18.4)
Controls: 499 randomly selected DNA samples from the Icelandic National Diet SurveyControls: (0.4%)
Eerola et al. (2001) [19]Cases: 107 Finnish hereditary breast cancer families defined as having three first- or second-degree relatives with breast or ovarian cancer at any ageNot assessedNot assessedSIR, 1.0 (95% CI, 0.0–3.9)SIR, 4.9 (95% CI, 1.8–11.0)
Controls: Finnish population based on gender, age, and calendar period–specific incidence rates
Cybulski et al. (2013) [20]Cases: 3,750 Polish men with prostate cancer unselected for age or family history and diagnosed between 1999 and 2012 Cases: 14 (0.4%)Not assessedAny BRCA1 mutation: OR, 0.9; (95% CI, 0.4–1.8)Not assessedProstate cancer risk was greater in familial cases and cases diagnosed <60 y.
4153delA: OR, 5.3 (95% CI, 0.6–45.2)
Controls: 3,956 Polish men with no history of cancer aged 23–90 yControls: 17 (0.4%) 5382insC: OR, 0.5 (95% CI, 0.2–1.3)
C61G: OR, 1.1 (95% CI, 1.6–2.2)

CI = confidence interval; OR = odds ratio; RR = relative risk; SIR = standardized incidence ratio.

These data suggest that prostate cancer risk in BRCA1/2 mutation carriers varies with the location of the mutation (i.e., there is a correlation between genotype and phenotype).[18,19,21] These observations might explain some of the inconsistencies encountered in prior studies of these associations, since varied populations may have differences in the proportion of persons with specific pathogenic BRCA1/2 mutations.

Several case series have also explored the role of BRCA1 and BRCA2 mutations and prostate cancer risk.

Table 10. Case Series of BRCA1 and BRCA2 and Prostate Cancer Risk

StudyPopulationMutation Freq. (BRCA1)Mutation Freq. (BRCA2)Prostate Cancer Risk (BRCA1)Prostate Cancer Risk (BRCA2)Comments
Agalliu et al. (2007) [22]290 men (white, n = 257; African American, n = 33) diagnosed with prostate cancer <55 y and unselected for family historyNot assessed2 (0.69%)Not assessedRR, 7.8 (95% CI, 1.8–9.4)No mutations were found in African American men.
The two men with a mutation reported no family history of breast cancer or ovarian cancer.
Agalliu et al. (2007) [23]266 individuals from 194 hereditary prostate cancer families, including 253 men affected with prostate cancer; median age at prostate cancer diagnosis: 58 yNot assessed0 (0%)Not assessedNot assessed31 nonsynonymous variations were identified; no truncating or deleterious mutations were detected.
Tryggvadóttir et al. (2007) [24]527 men diagnosed with prostate cancer between 1955 and 2004Not assessed30/527 (5.7%) carried the Icelandic founder mutation 999del5Not assessedNot assessedThe BRCA2 999del5 mutation was associated with a lower mean age at prostate cancer diagnosis (69 vs. 74 y; P = .002)
Kote-Jarai et al. (2011) [25]1,832 men diagnosed with prostate cancer between ages 36 and 88 y who participated in the UK Genetic Prostate Cancer StudyNot assessedOverall: 19/1,832 (1.03%) Not assessedRR, 8.6a (95% CI, 5.1–12.6)MLPA was not used; therefore, the mutation frequency may be an underestimate, given the inability to detect large genomic rearrangements.
Prostate cancer diagnosed ≤55 y: 8/632 (1.27%)
Leongamornlert et al. (2012) [26]913 men with prostate cancer who participated in the UK Genetic Prostate Cancer Study; included 821 cases diagnosed between ages 36 and 65 y, regardless of family history, and 92 cases diagnosed >65 y with a family history of prostate cancerAll cases: 4/886 (0.45%) Not assessedRR, 3.75a (95% CI, 1.02–9.6)Not assessedQuality-control assessment after sequencing excluded 27 cases, resulting in 886 included in the final analysis.
Cases ≤65 y: 3/802 (0.37%)

CI = confidence interval; MLPA = multiplex ligation-dependent probe amplification; RR = relative risk.

aEstimate calculated using relative risk data in UK general population.

These case series confirm that mutations in BRCA1 and BRCA2 do not play a significant role in hereditary prostate cancer. However, germline mutations in BRCA2 account for some cases of early-onset prostate cancer, although this is estimated to be less than 1% of early-onset prostate cancers in the United States.[22]

Prostate cancer aggressiveness in BRCA mutation carriers

The studies summarized in Table 11 used similar case-control methods to examine features of prostate cancer aggressiveness among men with prostate cancer found to harbor a BRCA1/BRCA2 mutation.

Table 11. Case-Control Studies of BRCA1 and BRCA2 and Prostate Cancer Aggressiveness

StudyCases / ControlsGleason ScoreaPSAaTumor Stage or GradeaComments
Tryggvadóttir et al. (2007) [24]Cases: 30 men diagnosed with prostate cancer who were BRCA2 999del5 founder mutation carriersGleason score 7–10:Not assessedStage IV at diagnosis:
– Cases: 84%– Cases: 55.2%
Controls: 59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry the BRCA2 999del5 mutation – Controls: 52.7% – Controls: 24.6%
Agalliu et al. (2009) [16]Cases: 979 AJ men diagnosed with prostate cancer between 1978 and 2005 (mean and median year of diagnosis: 1996)Gleason score 7–10: Not assessedNot assessed
– BRCA1 185delAG mutation: OR, 3.54 (95% CI, 1.22–10.31)
Controls: 1,251 AJ men with no history of cancer– BRCA2 6174delT mutation: OR, 3.18 (95% CI, 1.37–7.34)
Edwards et al. (2010) [27]Cases: 21 men diagnosed with prostate cancer who harbored a BRCA2 mutation: 6 with early-onset disease (≤55 y) from a UK prostate cancer study and 15 unselected for age at diagnosis from a UK clinical seriesNot assessedPSA ≥25 ng/mL: HR, 1.39 (95% CI, 1.04–1.86)Stage T3: HR, 1.19 (95% CI, 0.68–2.05)
Stage T4: HR, 1.87 (95% CI, 1.00–3.48)
Grade 2: HR, 2.24 (95% CI, 1.03–4.88)
Controls: 1,587 age- and stage-matched men with prostate cancerGrade 3: HR, 3.94 (95% CI, 1.78–8.73)
Gallagher et al. (2010) [17]Cases: 832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which there were six BRCA1 mutation carriers and 20 BRCA2 mutation carriers Gleason score 7–10: Not assessedNot assessedThe BRCA1 5382insC founder mutation was not tested in this series.
Controls: 454 AJ men with no history of cancerBRCA2 6174delT mutation: HR, 2.63 (95% CI, 1.23–5.6; P = .001)
Thorne et al. (2011) [28]Cases: 40 men diagnosed with prostate cancer who were BRCA2 mutation carriers from 30 familial breast cancer families from Australia and New Zealand Gleason score ≥8:PSA 10–100 ng/mL:Stage ≥pT3 at presentation: BRCA2 mutation carriers were more likely to have high-risk disease by D’Amico criteria than were noncarriers (77.5% vs. 58.7%, P = .05).
– BRCA2 mutations: 35% (14/40)– BRCA2 mutations: 44.7% (17/38)
– BRCA2 mutations: 65.8% (25/38) – Controls: 27.9% (27/97)
PSA >101 ng/mL:
Controls: 97 men from 89 familial breast cancer families from Australia and New Zealand with prostate cancer and no BRCA mutation found in the family – Controls: 33.0% (25/97) – BRCA2 mutations: 10% (4/40)– Controls: 22.6% (21/97)
–Controls: 2.1% (2/97)
Castro et al. (2013) [29]Cases: 2,019 men diagnosed with prostate cancer from the United Kingdom, of whom 18 were BRCA1 mutation carriers and 61 were BRCA2 mutation carriers Gleason score >8:BRCA1 median PSA: 8.9 (range, 0.7–3,000)Stage ≥pT3 at presentation:Nodal metastasis and distant metastasis were higher in men with a BRCA mutation than in controls.
– BRCA1 mutations: 27.8% (5/18)– BRCA1: 38.9% (7/18)
– BRCA2 mutations: 37.7% (23/61) BRCA2 median PSA: 15.1 (range, 0.5–761)– BRCA2 : 49.2% (30/61)
Controls: 1,940 men who were BRCA1/2 noncarriers– Controls 15.4% (299/1,940)Controls median PSA: 11.3 (range, 0.2–7,800)– Controls: 31.7% (616/1,940)
Akbari et al. (2014) [30]Cases: 4,187 men who underwent prostate biopsy for elevated PSA or abnormal exam, including 26 men with at least one BRCA coding mutation (all 26 coding exons of BRCA were sequenced for polymorphisms)Gleason score 7–10:Cases median PSA: 56.3Not fully assessed in cases and controlsThe 12-year survival for men with a BRCA2 mutation was inferior to that of men without a BRCA2 mutation (61.8% vs. 94.3%; P < 10−4). Among the men with high-grade disease (Gleason 7–9), the presence of a BRCA2 mutation was associated with an HR of 4.38 (95% CI, 1.99–9.62; P < .0001) after adjusting for age and PSA level.
– Cases 96%
Controls: 1,878 men with no BRCA coding mutations (all 26 coding exons of BRCA were sequenced for polymorphisms) – Controls 54% Controls median PSA: 13.3

AJ = Ashkenazi Jewish; CI = confidence interval; HR = hazard ratio; OR = odds ratio; PSA = prostate-specific antigen.

aMeasures of prostate cancer aggressiveness.

These studies suggest that prostate cancer in BRCA mutation carriers may be associated with features of aggressive disease, including higher Gleason score, higher prostate-specific antigen (PSA) level at diagnosis, and higher tumor stage and/or grade at diagnosis, a finding that warrants consideration as patients undergo cancer risk assessment and genetic counseling.[31]

BRCA1/BRCA2 and survival outcomes

Analyses of prostate cancer cases in families with known BRCA1 or BRCA2 mutations have been examined for survival. In an unadjusted analysis performed on a case series, median survival was 4 years in 183 men with prostate cancer with a BRCA2 mutation and 8 years in 119 men with a BRCA1 mutation. The study suggests that BRCA2 mutation carriers have a poorer survival than BRCA1 mutation carriers.[32] To further assess this observation, case-control studies were conducted (summarized in Table 12).

Table 12. Case-Control Studies of BRCA1 and BRCA2 and Survival Outcomes

StudyCasesControlsProstate Cancer–Specific SurvivalOverall SurvivalComments
Tryggvadóttir et al. (2007) [24]30 men diagnosed with prostate cancer who were BRCA2 999del5 founder mutation carriers59 men with prostate cancer matched by birth and diagnosis year and confirmed not to carry the BRCA2 999del5 mutation BRCA2 999del5 mutation was associated with a higher risk of death from prostate cancer (HR, 3.42; 95% CI, 2.12–5.51), which remained after adjustment for tumor stage and grade (HR, 2.35; 95% CI, 1.08–5.11).Not assessed
Edwards et al. (2010) [27] 21 men diagnosed with prostate cancer who harbored a BRCA2 mutation: 6 with early-onset disease (≤55 y) from a UK prostate cancer study and 15 unselected for age at diagnosis from a UK clinical series1,587 age- and stage-matched men with prostate cancer Not assessedOverall survival was lower in BRCA2 mutation carriers (4.8 y) than in noncarriers (8.5 y); in noncarriers, HR, 2.14 ( 95% CI, 1.28–3.56; P = .003).
Gallagher et al. (2010) [17]832 AJ men diagnosed with localized prostate cancer between 1988 and 2007, of which there were 6 BRCA1 mutation carriers and 20 BRCA2 mutation carriers454 AJ men with no history of cancerAfter adjusting for stage, PSA, Gleason score, and therapy received: Not assessedThe BRCA1 5382insC founder mutation was not tested in this series.
– BRCA1 185delAG mutation carriers had a greater risk of death due to prostate cancer (HR, 5.16; 95% CI, 1.09–24.53; P = .001).
– BRCA2 6174delT mutation carriers had a greater risk of death due to prostate cancer (HR, 5.48; 95% CI, 2.03–14.79; P = .001).
Thorne et al. (2011) [28]40 men diagnosed with prostate cancer who were BRCA2 mutation carriers from 30 familial breast cancer families from Australia and New Zealand 97 men from 89 familial breast cancer families from Australia and New Zealand with prostate cancer and no BRCA mutation found in the family BRCA2 carriers were shown to have an increased risk of prostate cancer–specific mortality (HR, 4.5; 95% CI, 2.12–9.52; P = 8.9 × 10-5), compared with noncarrier controls.BRCA2 carriers were shown to have an increased risk of death (HR, 3.12; 95% CI, 1.64–6.14; P = 3.0 × 10-4), compared with noncarrier controls.There were too few BRCA1 carriers available to include in the analysis.
Castro et al. (2013) [29]2,019 men diagnosed with prostate cancer from the UK, of whom 18 were BRCA1 mutation carriers and 61 were BRCA2 mutation carriers 1,940 men who were BRCA1/2 noncarriersProstate cancer–specific survival at 5 years: Overall survival at 5 years:For localized prostate cancer, metastasis-free survival was also higher in controls than in mutation carriers (93% vs. 77%; HR, 2.7).
– BRCA1: 80.8 (95% CI, 56.9–100)– BRCA1: 82.5 (95% CI, 60.4–100)
– BRCA2: 67.9 (95% CI 53.4–82.4)– BRCA2: 57.9 (95% CI, 43.4–72.4)
– Controls: 90.6 (95% CI 88.8–92.4)– Controls: 86.4 (95% CI, 84.4–88.4)

CI = confidence interval; HR = hazard ratio; PSA = prostate-specific antigen.

These findings suggest overall survival and prostate cancer–specific survival may be lower in mutation carriers than in controls.

Additional studies involving the BRCA region

A genome-wide scan for hereditary prostate cancer using 175 families from the University of Michigan Prostate Cancer Genetics Project (UM-PCGP) found evidence of linkage to chromosome 17q markers.[33] The maximum logarithm of the odds (LOD) score in all families was 2.36, and the LOD score increased to 3.27 when only families with four or more confirmed affected men were analyzed. The linkage peak was centered over the BRCA1 gene. In follow-up, these investigators screened the entire BRCA1 gene for mutations using DNA from one individual from each of 93 pedigrees with evidence of prostate cancer linkage to 17q markers.[34] Sixty-five of the individuals screened had wild-type BRCA1 sequence, and only one individual from a family with prostate and ovarian cancers was found to have a truncating mutation (3829delT). The remainder of the individuals harbored one or more germline BRCA1 variants, including 15 missense variants of uncertain clinical significance. The conclusion from these two reports is that there is evidence of a prostate cancer susceptibility gene on chromosome 17q near BRCA1; however, large deleterious inactivating mutations in BRCA1 are not likely to be associated with prostate cancer risk in chromosome 17–linked families.

In another study from the UM-PCGP, common genetic variation in BRCA1 was examined.[35] Conditional logistic regression analysis and family-based association tests were performed in 323 familial prostate cancer families and early-onset prostate cancer families, which included 817 men with and without prostate cancer, to investigate the association of single nucleotide polymorphisms (SNPs) tagging common haplotype variation in a 200-kilobase region surrounding and including BRCA1. Three SNPs in BRCA1 (rs1799950, rs3737559, and rs799923) were found to be associated with prostate cancer. The strongest association was observed for SNP rs1799950 (odds ratio [OR], 2.25; 95% CI, 1.21–4.20), which leads to a glutamine-to-arginine substitution at codon 356 (Gln356Arg) of exon 11 of BRCA1. Furthermore, SNP rs1799950 was found to contribute to the linkage signal on chromosome 17q21 originally reported by the UM-PCGP.[33]

Mismatch Repair (MMR) Genes

Four genes are implicated in MMR, namely MLH1, MSH2, MSH6, and PMS2. Germline mutations in these four genes have been associated with Lynch syndrome, which manifests by cases of nonpolyposis colorectal cancer and a constellation of other cancers in families, including endometrial, ovarian, and duodenal cancers; and transitional cell cancers of the ureter and renal pelvis. Reports have suggested that prostate cancer may be observed in men harboring an MMR gene mutation.[36,37] The first quantitative study described nine cases of prostate cancer occurring in a population-based cohort of 106 Norwegian male MMR mutation carriers or obligate carriers.[38] The expected number of cases among these 106 men was 1.52 (P < .01); the men were younger at the time of diagnosis (60.4 years vs. 66.6 years, P = .006) and had more evidence of Gleason score of 8 to 10 (P < .00001) than the cases from the Norwegian Cancer Registry. Kaplan Meier analysis revealed that the cumulative risk of prostate cancer diagnosis by age 70 years was 30% in MMR gene mutation carriers and 8% in the general population. This finding awaits confirmation in additional populations. A population-based case-control study examined haplotype-tagging SNPs in three MMR genes (MLH1, MSH2, and PMS2). This study provided some evidence supporting the contribution of genetic variation in MLH1 and overall risk of prostate cancer.[39] To assess the contribution of prostate cancer as a feature of Lynch Syndrome, one study performed microsatellite instability (MSI) testing on prostate cancer tissue blocks from families enrolled in a prostate cancer family registry who also reported a history of colon cancer. Among 35 tissue blocks from 31 distinct families, two tumors from MMR mutation–positive families were found to be MSI-high. The authors conclude that MSI is rare in hereditary prostate cancer.[40]

One study that included two familial cancer registries found an increased cumulative incidence and risk of prostate cancer among 198 independent mutation-positive families with Lynch syndrome.[41] The cumulative lifetime risk of prostate cancer (to age 80 years) was 30.0% in MMR mutation carriers (95% CI, 16.54–41.30; P = .07), whereas it was 17.84% in the general population, according to the Surveillance, Epidemiology, and End Results Program estimates. There was a trend of increased prostate cancer risk in mutation carriers by age 50 years, where the risk was 0.64% (95% CI, 0.24–1.01; P = .06), compared with a risk of 0.26% in the general population. Overall, the hazard ratio (HR) (to age 80 years) for prostate cancer in MMR mutation carriers in the combined data set was 1.99 (95% CI, 1.31–3.03; P = .0013). Among men aged 20 to 59 years, the HR was 2.48 (95% CI, 1.34–4.59; P = .0038).

A systematic review and meta-analysis that included 23 studies (6 studies with molecular characterization and 18 risk studies, of which 12 studies quantified risk for prostate cancer) reported an association of prostate cancer with Lynch syndrome.[42] In the six molecular studies included in the analysis, 73% (95% CI, 57%–85%) of prostate cancers in mutation carriers were MMR deficient. The relative risk of prostate cancer in MMR gene mutation carriers was estimated to be 3.67 (95% CI, 2.32–6.67). Of the twelve risk studies, the relative risk of prostate cancer ranged from 2.11 to 2.28, compared with that seen in the general population depending on carrier status, prior diagnosis of colorectal cancer, or unknown male carrier status from mutation-carrying families.

Although the risk of prostate cancer appears to be elevated in families with Lynch syndrome, strategies for germline testing for MMR gene mutations in index prostate cancer patients remain to be determined.

HOXB13

Linkage to 17q21-22 was initially reported by the UM-PCGP from 175 pedigrees of families with hereditary prostate cancer.[33] Fine-mapping of this region provided strong evidence of linkage (LOD score = 5.49) and a narrow candidate interval (15.5 Mb) for a putative susceptibility gene among 147 families with four or more affected men and average age at diagnosis of 65 years or younger.[43] The exons of 200 genes in the 17q21-22 region were sequenced in DNA from 94 unrelated patients from hereditary prostate cancer families (from the UM-PCGP and Johns Hopkins).[44] Probands from four families were discovered to have a recurrent mutation (G84E) in HOXB13, and 18 men with prostate cancer from these four families carried the mutation. The mutation status was determined in 5,083 additional case subjects and 2,662 control subjects. Carrier frequencies and ORs for prostate cancer risk were as follows:

  • Men with a positive family history of prostate cancer: 2.2% versus negative: 0.8% (OR, 2.8; 95% CI, 1.6–5.1; P = 1.2 × 10-4).
  • Men younger than 55 years at diagnosis: 2.2% versus older than 55 years: 0.8% (OR, 2.7; 95% CI, 1.6–4.7; P = 1.1 × 10-4).
  • Men with a positive family history of prostate cancer and younger than 55 years at diagnosis : 3.1% versus a negative family history of prostate cancer and age at diagnosis older than 55 years: 0.6% (OR, 5.1; 95% CI, 2.4–12.2; P = 2.0 × 10-6).
  • Men with a positive family history of prostate cancer and older than 55 years age at diagnosis: 1.2%.
  • Control subjects: 0.1% to 0.2%.[44]

A validation study from the International Consortium of Prostate Cancer Genetics confirmed HOXB13 as a susceptibility gene for prostate cancer risk.[45] Within carrier families, the G84E mutation was more common among men with prostate cancer than among unaffected men (OR, 4.42; 95% CI, 2.56–7.64). The G84E mutation was also significantly overtransmitted from parents to affected offspring (P = 6.5 × 10-6).

Additional studies have emerged that better define the carrier frequency, prostate cancer risk, and penetrance associated with the HOXB13 G84E mutation. To date, this mutation appears to be restricted to white men, primarily of European descent.[44,46-48] The highest carrier frequency of 6.25% was reported in Finnish early-onset cases.[49] A pooled analysis that included 9,016 cases and 9,678 controls of European Americans found an overall G84E mutation frequency of 1.34% among cases and 0.28% among controls.[50]

Risk of prostate cancer by HOXB13 G84E mutation status has been reported to vary by age of onset, family history, and geographical region. A validation study in an independent cohort of 9,988 cases and 61,994 controls from six studies of men of European ancestry, including 4,537 cases and 54,444 controls from Iceland whose genotypes were largely imputed, reported an OR of 7.06 (95% CI, 4.62–10.78; P = 1.5 × 10−19) for prostate cancer risk by G84E carrier status.[51] A pooled analysis reported a prostate cancer OR of 4.86 (95% CI, 3.18–7.69; P = 3.48 × 10-17) in men with HOXB13 mutations compared with noncarriers; this increased to an OR of 8.41 (95% CI, 5.27–13.76; P = 2.72 ×10-22) among men diagnosed with prostate cancer at age 55 years or younger. The OR was 7.19 (95% CI, 4.55–11.67; P = 9.3 × 10-21) among men with a positive family history of prostate cancer and 3.09 (95% CI, 1.83–5.23; P = 6.26 × 10-6) among men with a negative family history of prostate cancer.[50] A meta-analysis that included 24,213 cases and 73,631 controls of European descent revealed an overall OR for prostate cancer by carrier status of 4.07 (95% CI, 3.05–5.45; P < .00001). Risk of prostate cancer varied by geographical region: United States (OR, 5.10; 95% CI, 3.21–8.10; P < .00001), Canada (OR, 5.80; 95% CI, 1.27–26.51; P = .02), Northern Europe (OR, 3.61; 95% CI, 2.81–4.64; P < .00001), and Western Europe (OR, 8.47; 95% CI, 3.68–19.48; P < .00001).[47] In addition, the association between the G84E mutation and prostate cancer risk was higher for early-onset cases (OR, 10.11; 95% CI, 5.97–17.12). There was no significant association with aggressive disease in the meta-analysis. One population-based, case-control study from the United States confirmed the association of the G84E mutation with prostate cancer (OR, 3.30; 95% CI, 1.21–8.96) and reported a suggestive association with aggressive disease.[52] In addition, one study identified no men of Ashkenazi Jewish ancestry who carried the G84E mutation.[53] A case-control study from the U.K. that included 8,652 cases and 5,252 controls also confirmed the association of HOXB13 G84E with prostate cancer (OR, 2.93; 95% CI, 1.94–4.59; P = 6.27 × 10-8).[54] The risk was higher among men with a family history (OR, 4.53; 95% CI, 2.86–7.34; P = 3.1 × 10−8] and in early-onset prostate cancer (diagnosed at age 55 years or younger) ( OR, 3.11; 95% CI, 1.98–5.00; P = 6.1 × 10−7). No association was found between carrier status and Gleason score, cancer stage, overall survival, or cancer-specific survival.

Penetrance estimates for prostate cancer development in HOXB13 G84E mutation carriers are also being reported. One study from Sweden estimated a 33% lifetime risk of prostate cancer among G84E carriers.[55] Another study from Australia reported age-specific cumulative risk of prostate cancer of up to 60% by age 80 years.[56]

HOXB13 plays a role in prostate cancer development and interacts with the androgen receptor; however, the mechanism by which it contributes to the pathogenesis of prostate cancer remains unknown. This is the first gene identified to account for a fraction of hereditary prostate cancer, particularly early-onset prostate cancer. The clinical utility and implications for genetic counseling regarding the HOXB13 G84E mutation have yet to be defined.

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Interventions in Familial Prostate Cancer

Background

Decisions about risk-reducing interventions for patients with an inherited predisposition to prostate cancer, as with any disease, are best guided by randomized controlled clinical trials and knowledge of the underlying natural history of the process. However, existing studies of screening for prostate cancer in high-risk men (men with a positive family history of prostate cancer and African American men) are predominantly based on retrospective case series or retrospective cohort analyses. Because awareness of a positive family history can lead to more frequent work-ups for cancer and result in apparently earlier prostate cancer detection, assessments of disease progression rates and survival after diagnosis are subject to selection, lead time, and length biases. (Refer to the PDQ Cancer Screening Overview summary for more information.) This section focuses on screening and risk reduction of prostate cancer among men predisposed to the disease; data relevant to screening in high-risk men are primarily extracted from studies performed in the general population.

Screening

Information is limited about the efficacy of commonly available screening tests such as the digital rectal exam (DRE) and serum prostate-specific antigen (PSA) in men genetically predisposed to developing prostate cancer. Furthermore, comparing the results of studies that have examined the efficacy of screening for prostate cancer is difficult because studies vary with regard to the cut-off values chosen for an elevated PSA test. For a given sensitivity and specificity of a screening test, the positive predictive value (PPV) increases as the underlying prevalence of disease rises. Therefore, it is theoretically possible that the PPV and diagnostic yield will be higher for the DRE and for PSA in men with a genetic predisposition than in average-risk populations.[1,2]

Most retrospective analyses of prostate cancer screening cohorts have reported PPV for PSA, with or without DRE, among high-risk men in the range of 23% to 75%.[2-6] Screening strategies (frequency of PSA measurements or inclusion of DRE) and PSA cutoff for biopsy varied among these studies, which may have influenced this range of PPV. Cancer detection rates among high-risk men have been reported to be in the range of 4.75% to 22%.[2,5,6] Most cancers detected were of intermediate Gleason score (5–7), with Gleason scores of 8 or higher being detected in some high-risk men. Overall, there is limited information about the net benefits and harms of screening men at higher risk of prostate cancer. In addition, there is little evidence to support specific screening approaches in prostate cancer families at high risk. Risks and benefits of routine screening in the general population are discussed in the PDQ Prostate Cancer Screening summary. On the basis of the available data, most professional societies and organizations recommend that high-risk men engage in shared decision-making with their health care providers and develop individualized plans for prostate cancer screening based on their risk factors. A summary of prostate cancer screening recommendations for high-risk men by professional organizations is shown in Table 13.

Table 13. Summary of Prostate Cancer Screening Recommendations for High-Risk Men

Screening Recommendation SourcePopulationTestAge Screening InitiatedFrequencyComments
United States Preventive Services Task Force (2012) [7] No specific recommendation for high-risk populations (defined as black men and men with a prostate cancer family history).
American College of Physicians (2013) [8] African American men and men with first-degree relative diagnosed with prostate cancer, especially <65 yPSA≥45 y No clear evidence to establish screening frequency Counseling includes information about the uncertainties, risks, and potential benefits associated with prostate cancer screening.
No clear evidence to perform PSA test more frequently than every 4 y
Men with family history of multiple family members with prostate cancer diagnosed <65 yPSA≥40 y
PSA level >2.5 µg/L may warrant annual screening
American Urological Association (2013) [9]African American men and men with a strong prostate cancer family historyPSA>40 to <55 yIndividualized based on personal preferences and informed discussion regarding the uncertainty of benefit and associated harms.
American Cancer Society (2014) [10] African American men and/or men with a father or brother with prostate cancer diagnosed <65 yPSA with or without DREa ≥45 y Frequency depends on PSA levelCounseling consists of a review of the benefits and limitations of testing so that a clinician-assisted, informed decision about testing can be made.
Men with multiple family members with prostate cancer diagnosed <65 yPSA with or without DREa≥40 y Frequency depends on PSA level
NCCN (2014) [11]African American men and men with family history of prostate cancer PSA with or without DREbBaseline age 45–49 yEvery 1–2 y if DRE within normal limits AND PSA level >1 ng/mLCounseling includes:
Repeat testing at age 50 y if DRE within normal limits AND PSA level ≤1 ng/mL– Screening purpose is to detect aggressive prostate cancer.
50–70 y Every 1–2 y if DRE within normal limits AND PSA level <3 ng/mL– Screening usually identifies low risk cancers that can be managed through close surveillance.
>70 ycEvery 1–2 y if DRE within normal limits AND PSA level <3 ng/mL
NCCN (2014, 2015) [11,12]Men with BRCA1 deleterious mutationPSA with or without DREbConsider screening starting at age ≥40 yEvery 1–2 y
Men with BRCA2 deleterious mutationPSA with or without DREb≥40 yEvery 1–2 y

DRE = digital rectal exam; NCCN = National Comprehensive Cancer Network; PSA = prostate-specific antigen.

aDRE is recommended in addition to PSA test for men with hypogonadism.

bDRE not performed as a stand-alone screening exam. Performed in men with an elevated PSA and as a baseline exam in men with PSA levels within normal limits.

cScreening performed with caution and limited to men in good health with little or no comorbidities.

Level of evidence: 5

Screening in BRCA mutation carriers

An international study that focused on prostate cancer screening in BRCA1/2 mutation carriers versus noncarriers reported initial screening results.[13] The study recruited 2,481 men (791 BRCA1 carriers, 531 BRCA1 noncarriers; 731 BRCA2 carriers, 428 BRCA2 noncarriers). A total of 199 men (8%) presented with PSA levels higher than 3.0 ng/mL, which was the study PSA cutoff for recommending a biopsy. The overall cancer detection rate was 36.4% (59 prostate cancers diagnosed among 162 biopsies). Prostate cancer by BRCA mutation status was as follows: BRCA1 carriers (n = 18), BRCA1 noncarriers (n = 10); BRCA2 carriers (n = 24), BRCA2 noncarriers (n = 7). Using published stage and grade criteria for risk classification,[14] intermediate- or high-risk tumors were diagnosed in 11 of 18 BRCA1 carriers (61%), 8 of 10 BRCA1 noncarriers (80%), 17 of 24 BRCA2 carriers (71%), and 3 of 7 BRCA2 noncarriers (43%). The PPV of PSA with a biopsy threshold of 3.0 ng/mL was 48% in BRCA2 mutation carriers, 33.3% in BRCA2 noncarriers, 37.5% in BRCA1 carriers, and 23.3% in BRCA1 noncarriers. Ninety-five percent of the men were white; therefore, the results cannot be generalized to all ethnic groups. Follow-up for this study is ongoing.

Level of evidence (screening in BRCA mutation carriers): 3

Chemoprevention of prostate cancer with finasteride and dutasteride in men at high risk

The benefits, harms, and supporting data regarding the use of finasteride and dutasteride for the prevention of prostate cancer are discussed more extensively in the PDQ summary on Prostate Cancer Prevention. Here, the reported benefits and harms and the use in men at high risk of prostate cancer are summarized.

Finasteride and dutasteride were studied for the prevention of prostate cancer in randomized controlled trials. The Prostate Cancer Prevention Trial (PCPT) studied finasteride and included 9,060 participants in the reported analysis;[15] the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial evaluated dutasteride and included 8,231 participants.[16] A small subset of the participants in these studies were men with a family history of prostate cancer or men of African descent. Men with a family history of prostate cancer represented 16.7% of participants in the PCPT and 13% of participants in the REDUCE trial. African American men represented 3.3% of PCPT participants and 2.3% of REDUCE participants. Overall, finasteride and dutasteride reduced the incidence of prostate cancer, but the evidence is inadequate to determine whether there is a reduction in mortality with these agents.[15,16] In the PCPT trial, absolute reduction in incidence for more than 7 years with finasteride was 6% (24.4% with placebo and 18.4% with finasteride); relative risk reduction (RRR) for incidence was 24.8% (95% confidence interval [CI], 18.6%–30.6%). There was no difference in the number of men who died from prostate cancer in the two groups, although the number of deaths was low. In the REDUCE trial, absolute risk reduction with dutasteride was 5.1% at 4 years, and the RRR was 22.8% (95% CI, 15.2%–29.8%; P < .001). There was no difference in prostate cancer–specific or overall mortality, although the number of deaths was low. Subgroup analysis from the PCPT by race/ethnicity, age, and family history of prostate cancer showed no difference in efficacy of finasteride within any of these subgroups.

Harms of finasteride and dutasteride include increased rates of erectile dysfunction, loss of libido, decreased volume of ejaculate, and gynecomastia. Both finasteride and dutasteride were associated with increased rates of high-grade prostate cancer (finasteride study: 6.4% in finasteride group vs. 5.1% in placebo group; years 3 through 4 of dutasteride study: 0.5% in dutasteride group vs. <0.1% in placebo group). In the dutasteride study, evaluating rates of high-grade prostate cancer over all 4 years revealed no significant difference by study arm (0.9% in dutasteride group vs. 0.6% in placebo group). Table 14 summarizes the findings from these two studies.

Table 14. Randomized Controlled Trials (RCTs) Examining the Efficacy of 5-Alpha-Reductase Inhibitors in Prostate Cancer Chemopreventiona

PCPT (Finasteride) [15] REDUCE (Dutasteride) [16]
Duration of RCT 7 y4 y
No. of participants included in analysis9,0608,231
– % with FH of prostate cancer16.7%13.0%
– % African American3.3%2.3%
Benefits
– Absolute risk reduction in incidence6%5.1%
– Relative risk reduction in incidence24.8%22.8%
– Prostate cancer mortalityNo differenceNo difference
Harms
– Incidence of high-grade prostate cancerb6.4% (finasteride) vs. 5.1% (placebo)0.9% (dutasteride) vs. 0.6% (placebo)
– Side effectsDecreased volume ejaculateDecreased volume ejaculate
Decreased libidoDecreased libido
Erectile dysfunctionErectile dysfunction
GynecomastiaGynecomastia

FH = family history; PCPT = Prostate Cancer Prevention Trial; REDUCE = Reduction by Dutasteride of Prostate Cancer Events trial.

aThis table summarizes the first two RCTs of finasteride and dutasteride in prostate cancer chemoprevention.

bHigh-grade prostate cancer is defined as a Gleason score ≥7 in PCPT and a Gleason score ≥8 in REDUCE.

Level of evidence: 1aii

The American Society of Clinical Oncology and the American Urological Association issued joint recommendations regarding the use of 5-alpha-reductase inhibitors (5-ARIs) (i.e., finasteride and dutasteride) for prostate cancer prevention after a systematic literature review.[17] The guidelines state that asymptomatic men with a PSA level of 3.0 ng/mL or lower who regularly undergo PSA screening or men who anticipate undergoing annual PSA screening for early detection of prostate cancer may benefit from a discussion of the benefits of taking 5-ARIs for 7 years for the prevention of prostate cancer and its potential risks (including the possibility of high-grade prostate cancer) to enable them to make a better-informed decision. Men who are taking 5-ARIs for benign conditions associated with lower urinary tract symptoms may also benefit from a similar discussion. Points recommended to include in the physician-patient discussions were: (1) inform the men who are considering using 5-ARIs that these agents reduce the incidence of prostate cancer but do not reduce the risk of prostate cancer to zero; (2) discuss the elevated rate of high-grade cancer and inform men of the potential explanations; (3) make it known to men that no information about the long-term effects of 5-ARIs on prostate cancer incidence exists beyond approximately 7 years, and that whether or not a 5-ARI reduces prostate cancer mortality or increases life expectancy remains unknown; (4) inform men of possible but reversible sexual adverse effects; and (5) inform men of the likely improvement in lower urinary tract symptoms. No specific recommendations were made for high-risk men based on the evidence review.

Summary

On the basis of available evidence and guidelines, men with a family history of prostate cancer and men of African descent may benefit from engaging in shared decision-making regarding prostate cancer screening. Optimal screening strategies for high-risk men are yet to be determined. Although high-risk men may consider 5-ARIs for prostate cancer prevention, it is important to note that the U.S. Food and Drug Administration has not approved finasteride or dutasteride for the indication of prostate cancer prevention, and an in-depth discussion of the risks and benefits is warranted.

References

  1. Sartor O: Early detection of prostate cancer in African-American men with an increased familial risk of disease. J La State Med Soc 148 (4): 179-85, 1996. [PubMed: 8935621]
  2. Matikainen MP, Schleutker J, Mörsky P, et al.: Detection of subclinical cancers by prostate-specific antigen screening in asymptomatic men from high-risk prostate cancer families. Clin Cancer Res 5 (6): 1275-9, 1999. [PubMed: 10389909]
  3. Catalona WJ, Antenor JA, Roehl KA, et al.: Screening for prostate cancer in high risk populations. J Urol 168 (5): 1980-3; discussion 1983-4, 2002. [PubMed: 12394689]
  4. Valeri A, Cormier L, Moineau MP, et al.: Targeted screening for prostate cancer in high risk families: early onset is a significant risk factor for disease in first degree relatives. J Urol 168 (2): 483-7, 2002. [PubMed: 12131293]
  5. Narod SA, Dupont A, Cusan L, et al.: The impact of family history on early detection of prostate cancer. Nat Med 1 (2): 99-101, 1995. [PubMed: 7585019]
  6. Giri VN, Beebe-Dimmer J, Buyyounouski M, et al.: Prostate cancer risk assessment program: a 10-year update of cancer detection. J Urol 178 (5): 1920-4; discussion 1924, 2007. [PubMed: 17868726]
  7. Moyer VA; U.S. Preventive Services Task Force: Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 157 (2): 120-34, 2012. [PubMed: 22801674]
  8. Qaseem A, Barry MJ, Denberg TD, et al.: Screening for prostate cancer: a guidance statement from the Clinical Guidelines Committee of the American College of Physicians. Ann Intern Med 158 (10): 761-9, 2013. [PubMed: 23567643]
  9. Carter HB, Albertsen PC, Barry MJ, et al.: Early detection of prostate cancer: AUA Guideline. J Urol 190 (2): 419-26, 2013. [PMC free article: PMC4020420] [PubMed: 23659877]
  10. Smith RA, Manassaram-Baptiste D, Brooks D, et al.: Cancer screening in the United States, 2014: a review of current American Cancer Society guidelines and current issues in cancer screening. CA Cancer J Clin 64 (1): 30-51, 2014 Jan-Feb. [PubMed: 24408568]
  11. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer Early Detection. Version 1.2014. Rockledge, PA : National Comprehensive Cancer Network, 2014. Available online with free subscription. Last accessed June 17, 2014.
  12. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 1.2015. Rockledge, PA: National Comprehensive Cancer Network, 2015. Available online with free registration. Last accessed April 09, 2015.
  13. Bancroft EK, Page EC, Castro E, et al.: Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study. Eur Urol 66 (3): 489-99, 2014. [PMC free article: PMC4105321] [PubMed: 24484606]
  14. National Collaborating Centre for Cancer (UK): Prostate Cancer: Diagnosis and Treatment. Cardiff, UK: National Collaborating Centre for Cancer, 2008. Available online. Last accessed October 26, 2015.
  15. Thompson IM, Goodman PJ, Tangen CM, et al.: The influence of finasteride on the development of prostate cancer. N Engl J Med 349 (3): 215-24, 2003. [PubMed: 12824459]
  16. Andriole GL, Bostwick DG, Brawley OW, et al.: Effect of dutasteride on the risk of prostate cancer. N Engl J Med 362 (13): 1192-202, 2010. [PubMed: 20357281]
  17. Kramer BS, Hagerty KL, Justman S, et al.: Use of 5-alpha-reductase inhibitors for prostate cancer chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline. J Clin Oncol 27 (9): 1502-16, 2009. [PMC free article: PMC2668556] [PubMed: 19252137]

Prostate Cancer Risk Assessment

The purpose of this section is to describe current approaches to assessing and counseling patients about susceptibility to prostate cancer. Genetic counseling for men at increased risk of prostate cancer encompasses all of the elements of genetic counseling for other hereditary cancers. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.) The components of genetic counseling include concepts of prostate cancer risk, reinforcing the importance of detailed family history, pedigree analysis to derive age-related risk, and offering participation in research studies to those individuals who have multiple affected family members.[1,2] Genetic testing for prostate cancer susceptibility is not available outside of the context of a research study. Families with prostate cancer can be referred to ongoing research studies; however, these studies will not provide individual genetic results to participants.

Prostate cancer will affect an estimated one in seven American men during their lifetime.[3] Currently, evidence exists to support the hypothesis that approximately 5% to 10% of all prostate cancer is due to rare autosomal dominant prostate cancer susceptibility genes.[4,5] The proportion of prostate cancer associated with an inherited susceptibility may be even larger.[6-8] Men are generally considered to be candidates for genetic counseling regarding prostate cancer risk if they have a family history of prostate cancer. The Hopkins Criteria provide a working definition of hereditary prostate cancer families.[9] The three criteria include the following:

  1. Three or more first-degree relatives (father, brother, son), or
  2. Three successive generations of either the maternal or paternal lineages, or
  3. At least two relatives affected at or before age 55 years.

Families need to fulfill only one of these criteria to be considered to have hereditary prostate cancer. One study investigated attitudes regarding prostate cancer susceptibility among sons of men with prostate cancer.[10] They found that 90% of sons were interested in knowing whether there is an inherited susceptibility to prostate cancer and would be likely to undergo screening and consider genetic testing if there was a family history of prostate cancer; however, similar high levels of interest in genetic testing for other hereditary cancer syndromes have not generally been borne out in testing uptake once the clinical genetic test becomes available.

Risk Assessment and Analysis

Assessment of a man concerned about his inherited risk of prostate cancer should include taking a detailed family history; eliciting information regarding personal prostate cancer risk factors such as age, race, and dietary intake of fats and dairy products; documenting other medical problems; and evaluating genetics-related psychosocial issues.

Family history documentation is based on construction of a pedigree, and generally includes the following:

  • The history of cancer in both maternal and paternal bloodlines.
  • All primary cancer diagnoses (not just prostate cancer) and ages at diagnosis.
  • Race and ethnicity.
  • Other health problems including benign prostatic hypertrophy.[11]

(Refer to the Documenting the family history section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for a more detailed description of taking a family history.)

Analysis of the family history generally consists of four components:

  1. Evaluation of the pattern of cancers in the family to identify cancer clusters, which might suggest a known inherited cancer syndrome. In addition to site-specific prostate cancer, other cancer susceptibility syndromes include prostate cancer as a component tumor (e.g., hereditary breast/ovarian cancer syndrome [associated with mutations in BRCA1 and BRCA2]).
  2. Assessment for genetic transmission. The pedigree should be assessed for evidence of both autosomal dominant and X-linked inheritance, which may be associated with a higher likelihood of an inherited susceptibility to prostate cancer. Autosomal dominant transmission is characterized by the presence of affected family members in sequential generations, with approximately 50% of males in each generation affected with prostate cancer. X-linked inheritance is suggested by apparent transmission of susceptibility from affected males in the maternal lineage. (Refer to the Analysis of the Family History section in the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.)
  3. Age at diagnosis of prostate cancer in the family. An inherited susceptibility to prostate cancer may be likely in families with early-onset (inconsistently defined) prostate cancer.[12] However, genetic research is also underway in families with an older age of prostate cancer onset. In the aggregate, the data are inconsistent relative to whether hereditary prostate cancer is routinely characterized by a younger-than-usual age at diagnosis.
  4. Risk assessment based on family and epidemiological studies. Multiple studies have reported that first-degree relatives of men affected with prostate cancer are two to three times more likely to develop prostate cancer than are men in the general population. In some studies, the relative risk (RR) of prostate cancer is highest among families who develop prostate cancer at an earlier age, consistent with other cancer susceptibility syndromes in which early age at onset is a common feature. It has been estimated that male relatives of men diagnosed with prostate cancer younger than 53 years have a 40% lifetime cumulative risk of developing prostate cancer.[13] A population-based case-control study of more than 1,500 cases and 1,600 controls, in which whites, African Americans, and Asian Americans were studied, reported an odds ratio of 2.5 for men with an affected first-degree relative after adjusting for age and ethnicity.[14] For men with a brother and father or son affected with prostate cancer, the RR was estimated to be 6.4.

A number of studies have examined the accuracy of the family history of prostate cancer provided by men with prostate cancer. This has clinical importance when risk assessments are based on unverified family history information. In an Australian study of 154 unaffected men with a family history of prostate cancer, self-reported family history was verified from cancer registry data in 89.6% of cases.[15] Accuracy of age at diagnosis within a 3-year range was correct in 83% of the cases, and accuracy of age at diagnosis within a 5-year range was correct in 93% of the cases. Self-reported family history from men younger than 55 years and reports about first-degree relatives had the highest degree of accuracy.[15] Self-reported family history of prostate cancer, however, may not be reliably reported over time,[16] which underscores the need to verify objectively reported prostate cancer diagnoses when trying to determine whether a patient has a significant family history.

The personal health and risk-factor history includes, but is not limited to, the following:

  • Family history.
  • Current and past diet history, including fat intake.
  • Current and past use of drugs that can affect prostatic growth, such as steroids (e.g., finasteride [Proscar]). (Refer to the PDQ summary on Prostate Cancer Prevention for more information about finasteride and prostate cancer.)
  • Current and past use of complementary and alternative medications (e.g., saw palmetto, PC-SPES).[17] (Refer to the PDQ summary on PC-SPES for more information.)

The most definitive risk factors for prostate cancer are age, race, and family history.[18] The correlation between other risk factors and prostate cancer risk is not clearly established. Despite this limitation, cancer risk counseling is an educational process that provides details regarding the state of the knowledge of prostate cancer risk factors. The discussion regarding these other risk factors should be individualized to incorporate the patient's personal health and risk factor history. (Refer to the Risk Factors for Prostate Cancer section of this summary for a more detailed description of prostate cancer risk factors.)

The psychosocial assessment in this context might include evaluation of the following:

  • Level of psychological distress.
  • Perceived risk of prostate cancer.
  • Past history of depression, anxiety, or other mental illness.

One study found that psychological distress was greater among men attending prostate cancer screening who had a family history of the disease, particularly if they also reported an overestimation of prostate cancer risk. Psychological distress and elevated risk perception may influence adherence to cancer screening and risk management strategies. Consultation with a mental health professional may be valuable if serious psychosocial issues are identified.[19]

Genetic Testing

At this time, with the exception of prostate cancer in a family with evidence of hereditary breast/ovarian cancer (HBOC) syndrome, clinical genetic testing to detect inherited prostate cancer predisposition is not available. (Refer to the BRCA1 and BRCA2 section of this summary and the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information about prostate cancer in HBOC.) None of the candidate susceptibility genes have been unequivocally associated with prostate cancer predisposition. For families suspected of having an inherited susceptibility to prostate cancer, participation in ongoing research studies investigating the genetic basis of inherited prostate cancer susceptibility can be considered.

References

  1. Nieder AM, Taneja SS, Zeegers MP, et al.: Genetic counseling for prostate cancer risk. Clin Genet 63 (3): 169-76, 2003. [PubMed: 12694223]
  2. Bruner DW, Baffoe-Bonnie A, Miller S, et al.: Prostate cancer risk assessment program. A model for the early detection of prostate cancer. Oncology (Huntingt) 13 (3): 325-34; discussion 337-9, 343-4 pas, 1999. [PubMed: 10204154]
  3. American Cancer Society: Cancer Facts and Figures 2015. Atlanta, Ga: American Cancer Society, 2015. Available online. Last accessed October 30, 2015.
  4. Steinberg GD, Carter BS, Beaty TH, et al.: Family history and the risk of prostate cancer. Prostate 17 (4): 337-47, 1990. [PubMed: 2251225]
  5. Carter BS, Beaty TH, Steinberg GD, et al.: Mendelian inheritance of familial prostate cancer. Proc Natl Acad Sci U S A 89 (8): 3367-71, 1992. [PMC free article: PMC48868] [PubMed: 1565627]
  6. Lesko SM, Rosenberg L, Shapiro S: Family history and prostate cancer risk. Am J Epidemiol 144 (11): 1041-7, 1996. [PubMed: 8942435]
  7. Grönberg H, Damber L, Damber JE, et al.: Segregation analysis of prostate cancer in Sweden: support for dominant inheritance. Am J Epidemiol 146 (7): 552-7, 1997. [PubMed: 9326432]
  8. Schaid DJ, McDonnell SK, Blute ML, et al.: Evidence for autosomal dominant inheritance of prostate cancer. Am J Hum Genet 62 (6): 1425-38, 1998. [PMC free article: PMC1377141] [PubMed: 9585590]
  9. Carter BS, Bova GS, Beaty TH, et al.: Hereditary prostate cancer: epidemiologic and clinical features. J Urol 150 (3): 797-802, 1993. [PubMed: 8345587]
  10. Bratt O, Kristoffersson U, Lundgren R, et al.: Sons of men with prostate cancer: their attitudes regarding possible inheritance of prostate cancer, screening, and genetic testing. Urology 50 (3): 360-5, 1997. [PubMed: 9301698]
  11. Pienta KJ, Esper PS: Risk factors for prostate cancer. Ann Intern Med 118 (10): 793-803, 1993. [PubMed: 8470854]
  12. Giovannucci E: How is individual risk for prostate cancer assessed? Hematol Oncol Clin North Am 10 (3): 537-48, 1996. [PubMed: 8773495]
  13. Neuhausen SL, Skolnick MH, Cannon-Albright L: Familial prostate cancer studies in Utah. Br J Urol 79 (Suppl 1): 15-20, 1997. [PubMed: 9088268]
  14. Whittemore AS, Wu AH, Kolonel LN, et al.: Family history and prostate cancer risk in black, white, and Asian men in the United States and Canada. Am J Epidemiol 141 (8): 732-40, 1995. [PubMed: 7535977]
  15. Gaff CL, Aragona C, MacInnis RJ, et al.: Accuracy and completeness in reporting family history of prostate cancer by unaffected men. Urology 63 (6): 1111-6, 2004. [PubMed: 15183962]
  16. Weinrich SP, Faison-Smith L, Hudson-Priest J, et al.: Stability of self-reported family history of prostate cancer among African American men. J Nurs Meas 10 (1): 39-46, 2002 Spring-Summer. [PubMed: 12048968]
  17. Barqawi A, Gamito E, O'Donnell C, et al.: Herbal and vitamin supplement use in a prostate cancer screening population. Urology 63 (2): 288-92, 2004. [PubMed: 14972473]
  18. Stanford JL, Stephenson RA, Coyle LM, et al., eds.: Prostate Cancer Trends 1973-1995. Bethesda, Md: National Cancer Institute, 1999. NIH Pub. No. 99-4543. Also available online. Last accessed October 26, 2015.
  19. Taylor KL, DiPlacido J, Redd WH, et al.: Demographics, family histories, and psychological characteristics of prostate carcinoma screening participants. Cancer 85 (6): 1305-12, 1999. [PubMed: 10189136]

Psychosocial Issues in Familial Prostate Cancer

Introduction

Research to date has included survey, focus group, and correlation studies on psychosocial issues related to prostate cancer risk. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about psychological issues related to genetic counseling for cancer risk assessment.) When it becomes available, genetic testing for mutations in prostate cancer susceptibility genes has the potential to identify those at highest risk, which facilitates risk-reducing interventions and early detection of prostate cancer. Having an understanding of the motivations of men who may consider genetic testing for inherited susceptibility to prostate cancer will help clinicians and researchers anticipate interest in testing. Further, these data will inform the nature and content of counseling strategies for men and their families, including consideration of the risks, benefits, decision-making issues, and informed consent for genetic testing.

Risk Perception

Knowledge about risk of prostate cancer is thought to be a factor influencing men’s decisions to pursue prostate cancer screening and, possibly, genetic testing.[1] A study of 79 African American men (38 of whom had been diagnosed with prostate cancer and the remainder who were unaffected but at high risk of prostate cancer) completed a nine-item telephone questionnaire assessing knowledge about hereditary prostate cancer. On a scale of 0 to 9, with 9 representing a perfect score, scores ranged from 3.5 to 9 with a mean score of 6.34. The three questions relating to genetic testing were the questions most likely to be incorrect. In contrast, questions related to inheritance of prostate cancer risk were answered correctly by the majority of subjects.[2] Overall, knowledge of hereditary prostate cancer was low, especially concepts of genetic susceptibility, indicating a need for increased education. An emerging body of literature is now exploring risk perception for prostate cancer among men with and without a family history. Table 15 provides a summary of studies examining prostate cancer risk perception.

Table 15. Summary of Cross-Sectional Studies of Prostate Cancer Risk Perception

Study PopulationSample SizeProportion of Study Population That Accurately Reported Their Risk Other Findings
Unaffected men with a family history of prostate cancer [3]120 men aged 40–72 y40%
FDR of men with prostate cancer [4]105 men aged 40–70 y62%
Men with brothers affected with prostate cancer [5]111 men aged 33–78 yNot available38% of men reported their risk of prostate cancer to be the same or less than the average man.
FDR of men with prostate cancer and a community sample [6]56 men with an FDR with prostate cancer and 100 men without an FDR with prostate cancer all older than 40 y57%29% of men with an FDR thought that they were at the same risk as the average man, and 14% believed that they were at somewhat lower risk than average.

FDR = first-degree relative.

Study conclusions vary regarding whether first-degree relatives (FDRs) of prostate cancer patients accurately estimate their prostate cancer risk. Some studies found that men with a family history of prostate cancer considered their risk to be the same as or less than that of the average man.[5,6] Other factors, including being married, have been associated with higher prostate cancer risk perception.[7] A confounder in prostate cancer risk perception was confusion between benign prostatic hyperplasia and prostate cancer.[3]

Anticipated Interest in Genetic Testing for Risk of Prostate Cancer

A number of studies summarized in Table 16 have examined participants' interest in genetic testing, if such a test were available for clinical use. Factors found to positively influence the interest in genetic testing include the following:

  • Advice of their primary care physician.[8]
  • Combination of emotional distress and concern about prostate cancer treatment effects.[9]
  • Having children.[10]

Findings from these studies were not consistent regarding the influence of race, education, marital status, employment status, family history, and age on interest in genetic testing. Study participants expressed concerns about confidentiality of test results among employers, insurers, and family and stigmatization; potential loss of insurability; and the cost of the test.[8] These concerns are similar to those that have been reported in women contemplating genetic testing for breast cancer predisposition.[11-16] Concerns voiced about testing positive for a mutation in a prostate cancer susceptibility gene included decreased quality of life secondary to interference with sex life in the event of a cancer diagnosis, increased anxiety, and elevated stress.[8]

Table 16. Summary of Cross-Sectional Studies of Anticipated Interest in Prostate Cancer Susceptibility Genetic Testing

Study PopulationSample SizePercent Expressing Interest in Genetic TestingOther Findings
Prostate screening clinic participants [17]342 men aged 40–97 y89%28% did not demonstrate an understanding of the concept of inherited predisposition to cancer.
General population; 9% with positive family history [8]12 focus groups with a total of 90 men aged 18–70 yAll focus groups
African American men [18]320 men aged 21–98 y87%Most participants could not distinguish between genetic susceptibility testing and a prostate-specific antigen blood test.
Men with and without FDRs with prostate cancer [9]126 men aged >40 y; mean age 52.6 y24% definitely; 50% probably
Swedish men with an FDR with prostate cancer [3]110 men aged 40–72 y76% definitely; 18% probably89% definitely or probably wanted their sons to undergo genetic testing.
Sons of Swedish men with prostate cancer [10]101 men aged 21–65 y90%; 100% of sons with two or three family members affected with prostate cancer60% expressed worry about having an increased risk of prostate cancer.
Healthy outpatient males with no history of prostate cancer [19]400 men aged 40–69 y82%
Healthy African American males with no history of prostate cancer [20]413 African American men aged 40–70 y87%Belief in the efficacy of and intention to undergo prostate cancer screening was associated with testing interest.
Healthy Australian males with no history of prostate cancer [21]473 adult men66% definitely; 26% probably73% reported that they felt diet could influence prostate cancer risk.
Males with prostate cancer and their unaffected male family members [22]559 men with prostate cancer; 370 unaffected male relatives 45% of men affected with cancer; 56% of unaffected menIn affected men, younger age and test familiarity were predictors of genetic testing interest. In unaffected men, older age, test familiarity, and a PSA test within the last 5 y were predictors of genetic testing interest.

FDR = first-degree relative; PSA = prostate-specific antigen

Overall, these reports and a study that developed a conceptual model to look at factors associated with intention to undergo genetic testing [23] have shown a significant interest in genetic testing for prostate cancer susceptibility despite concerns about confidentiality and potential discrimination. These findings must be interpreted cautiously in predicting actual prostate cancer genetic test uptake once testing is available. In both Huntington disease and hereditary breast and ovarian cancers, hypothetical interest before testing was possible was much higher than actual uptake following availability of the test.[24,25]

In a sample comprised of undiagnosed men with and without a prostate cancer–affected FDR, older age and lower education levels were associated with lower levels of prostate cancer–specific distress (as measured by the 11-item Prostate Cancer Anxiety Subscale of the Memorial Anxiety Scale for Prostate Cancer); higher distress was associated with having more urinary symptoms.[26] In the same study, men with a prostate cancer–affected FDR who perceived their relative’s cancer as more threatening and who had a relative deceased from the disease reported higher distress. In general, prostate cancer–specific distress levels were low for both groups of men.

Screening for Prostate Cancer in Individuals at Increased Familial Risk

The proportion of prostate cancers attributed to hereditary causes is estimated to be 5% to 10%,[27] and the risk of prostate cancer increases with the number of blood relatives with prostate cancer and young age at onset of prostate cancer within families.[28] There is considerable controversy in prostate cancer about the use of serum prostate-specific antigen (PSA) measurement and digital rectal exam for prostate cancer early detection in the general population, with different organizations suggesting significantly different screening algorithms and age recommendations. (Refer to the PDQ summary on Prostate Cancer Treatment for more information about prostate cancer in the general population and the Interventions section of this summary for more information about inherited prostate cancer susceptibility.) This variation is likely to add to patient and provider confusion about recommendations for screening by members of hereditary cancer families or FDRs of prostate cancer patients. Psychosocial questions of interest include what individuals at increased risk understand about hereditary risk, whether informational interventions are associated with increased uptake of prostate cancer screening behaviors, and what the associated quality-of-life implications of screening are for individuals at increased risk. Also of interest is the role of the primary care provider in helping those at increased risk identify their risk and undergo age- and family-history–appropriate screening.

Screening behaviors

In most cancers, the goal of improved knowledge of hereditary risk can be translated rather easily into a desired increase in adherence to approved and recommended (if not proven) screening behaviors. This is complicated for prostate cancer screening by the lack of clear recommendations for men in both high-risk and general populations. (Refer to the Screening section of this summary for more information.) In addition, controversy exists with regard to the value of early diagnosis of prostate cancer. This creates uncertainty for patients and providers and challenges the psychosocial factors related to screening behavior.

Several small studies have examined the behavioral correlates of prostate cancer screening at average and increased prostate cancer risk based on family history; these are summarized in Table 17. In general, results appear contradictory regarding whether men with a family history are more likely to be screened than those not at risk and whether the screening is appropriate for their risk status. Furthermore, most of the studies had relatively small numbers of subjects, and the criteria for screening were not uniform, making generalization difficult.

Table 17. Summary of Studies of Behavioral Correlates for Prostate Cancer Screening

Study Population Sample Size Percent Undergoing Screening Predictive Correlates for Screening Behavior
Unaffected men with at least one FDR with prostate cancer [29]82 men (aged ≥40 y; mean age 50.5 y)PSA:Aged >50 y.
Annual income ≥ U.S. $40,000.
50% reported PSA screening within the previous 14 mo.History of PSA screening before study enrollment.
Higher levels of self-efficacy and response efficacy for undergoing prostate cancer screening.
Sons of men with prostate cancer [30]124 men (60 men with a history of prostate cancer aged 38–84 y, median age 59 y; 64 unaffected men aged 31–78 y, median age 55 y)PSA:39.4% patient request.
– Unaffected men: 95.3% reported ever having a PSA test.
– Affected men: 71.7% reported ever having a PSA test before diagnosis.
DRE:
– Unaffected men: 96.9% reported ever having a DRE.
– Affected men: 91.5% reported ever having a DRE before diagnosis.35.6% physician request.
Both PSA and DRE:
– Unaffected men: 93.8% had both procedures.
– Affected men: 70.0% reported having both procedures before diagnosis.
Unaffected men with and without an FDR with prostate cancer [6]156 men aged ≥40 y (56 men with an FDR; 100 men without an FDR)PSA:Older age.
63% reported ever having a PSA test.
FDRs reported higher disease vulnerability and less belief in disease prevention, but this did not result in increased prostate cancer screening when compared with those without an FDR.
DRE:
86% reported ever having a DRE.
Unaffected Swedish men from families with a 50% probability of carrying a mutation in a dominant prostate cancer susceptibility gene [3]110 men aged 50–72 y68% of men aged ≥50 y were screened for prostate cancer. More relatives with prostate cancer.
Low score on the avoidance subscales of the Impact of Event Scale.[31]
Brothers or sons of men with prostate cancer [32]136 men aged 40–70 y (72% were African American men)PSA:More relatives with prostate cancer.
72% reported ever having a PSA test.
– 73% within 1 y.Older age.
– 23% 1–2 y ago.
– 4% >2 y ago.
DRE:Urinary symptoms.
90% reported ever having had a DRE.
– 60% within 1 y.
– 23% 1–2 y ago.71% reported their physician had spoken to them about prostate cancer screening.
– 17% >2 y ago.
Unaffected men with and without an FDR with prostate cancer [33]166 men aged 40–80 y (83 men with an FDR; 83 men with no family history)PSA:Family history of prostate cancer.
– FDR: 72% reported ever having had a PSA test.
– No family history: 53% reported ever having had a PSA test.Greater perceived vulnerability to developing prostate cancer.
French brothers or sons of men with prostate cancer [34]420 men aged 40–70 yPSA:Younger age.
More relatives with prostate cancer.
Increased anxiety.
88% adhered to annual PSA screening.Married.
Higher education.
Previous history of prostate cancer screening.
Data from unaffected African American men participating in AAHPC and data from the 1998 and 2000 NHIS [35]Unaffected men aged 40–69 y:PSA:Younger age.
AAHPC Cohort:
– 45% reported ever having had a PSA test.
– AAHPC Cohort: 134 menAfrican American men in 2000 NHIS:
– 65% reported ever having had a PSA test.
DRE:
– NHIS 1998 Cohort: 5,583 men (683 African American, 4,900 white)AAHPC Cohort:Fewer relatives with prostate cancer.
– 35% reported ever having had a DRE.
African American men in 1998 NHIS:
– NHIS 2000 Cohort: 3,359 men (411 African American, 2,948 white)– 45% reported ever having had a DRE.
Unaffected African American men who participated in the 2000 NHIS [36]736 men aged ≥45 yPSA:Older age (≥50 y).
Private or military health insurance.
48% reported ever having had a PSA test.Fair or poor health status.
Family history of prostate cancer.

AAHPC = African American Hereditary Prostate Cancer Study Network; DRE = digital rectal exam; FDR = first-degree relative; NHIS = National Health Interview Survey; PSA = prostate-specific antigen.

Psychosocial outcomes of screening in individuals at increased familial risk

Concern about developing prostate cancer: Although up to 50% of men in some studies who were FDRs of prostate cancer patients expressed some concern about developing prostate cancer,[5] the level of anxiety reported is typically relatively low and is related to lifetime risk rather than short-term risk.[3,5] The concern is also higher in men who are younger than his FDR was at the time when their prostate cancer was diagnosed.[5] Unmarried FDRs worried more about developing prostate cancer than did married men.[5] Men with higher levels of concern about developing prostate cancer also had higher estimates of personal prostate cancer risk and had a larger number of relatives diagnosed with prostate cancer.[5] In a Swedish study, only 3% of the 110 men surveyed said that worry about prostate cancer affected their daily life “fairly much,” and 28% said it affected their daily life "slightly."[3]

Baseline distress levels: Among men who self-referred for free prostate cancer screening, general and prostate cancer–related distress did not differ significantly between men who were FDRs of prostate cancer patients and men who were not.[37] Men with a family history of prostate cancer in the study had higher levels of perceived risk. In a Swedish study, male FDRs of prostate cancer patients who reported more worry about developing prostate cancer had higher Hospital Anxiety and Depression Scale (HADS) depression and anxiety scores than men with lower levels of worry. In that study, the average HADS depression and anxiety scores among FDRs was at the 75th percentile. Depression was associated with higher levels of personal risk overestimation.[3]

Distress experienced during prostate cancer screening: A study measured the anxiety and general quality of life experienced by 220 men with a family history of prostate cancer while undergoing prostate cancer screening with PSA tests.[32] In this group, 20% of the men experienced a moderate deterioration in their anxiety scores, and 20% experienced a minimal deterioration in health-related quality of life (HRQOL). The average period between assessments was 35 days, which encompassed PSA testing and a wait for results that averaged 15.6 days. Only men with normal PSA values (4 ng/mL or less) were assessed. Factors associated with deterioration in HRQOL included being age 50 to 60 years, having more than two relatives with prostate cancer, having an anxious personality, being well-educated, and having no children presently living at home. These authors stress that analysis of the impact of screening on FDRs should not rely solely on mean changes in scores, which may “mask diversity among responses, as illustrated by the proportion of subjects worsening during the screening process.” Given that these were men receiving what was considered a normal result and that a subset of men experienced screening-associated distress, this study suggests that interventions to reduce screening-related distress may be needed to encourage men at increased hereditary risk to comply with repeated requests for screening.

A study in the United Kingdom assessed predictors of psychological morbidity and screening adherence in FDRs of men with prostate cancer participating in a PSA screening study. One hundred twenty-eight FDRs completed measures assessing psychological morbidity, barriers, benefits, knowledge of PSA screening, and perceived susceptibility to prostate cancer. Overall, 18 men (14%) scored above the threshold for psychiatric morbidity, consistent with normal population ranges. Cancer worry was positively associated with health anxiety, perceived risk, and subjective stress. However, psychological morbidity did not predict PSA screening adherence. Only past screening behavior was found to be associated with PSA screening adherence.[38]

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Changes to This Summary (10/02/2015)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Identifying Genes and Inherited Variants Associated With Prostate Cancer Risk

Revised text to state that to date, approximately 100 variants associated with prostate cancer have been identified by well-powered genome-wide association studies (GWAS) and validated in independent cohorts (cited Eeles et al. as reference 187).

Revised Table 6, Inherited Variants Associated With Prostate Cancer Aggressiveness, to include text about GWAS risk single-nucleotide polymorphism rs11672691 (cited Shui et al. as reference 234).

Genes With Potential Clinical Relevance in Prostate Cancer Risk

Added National Comprehensive Cancer Network as reference 31.

Added Haraldsdottir et al. as reference 37.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genetics of prostate cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

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Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Genetics of Prostate Cancer are:

  • Kathleen A. Calzone, PhD, RN, APNG, FAAN (National Cancer Institute)
  • Veda N. Giri, MD (Thomas Jefferson University)
  • Jennifer Lynn Hay, PhD (Memorial Sloan-Kettering Cancer Center)
  • Suzanne M. O'Neill, MS, PhD, CGC (Northwestern University)
  • Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)
  • Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
  • Mark Pomerantz, MD (Dana-Farber Cancer Institute)
  • Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
  • Catharine Wang, PhD, MSc (Boston University School of Public Health)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Genetics of Prostate Cancer. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/types/prostate/hp/prostate-genetics-pdq. Accessed <MM/DD/YYYY>.

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