Clinical characteristics.

MUTYH polyposis (also referred to as MUTYH-associated polyposis, or MAP) is characterized by a greatly increased lifetime risk of colorectal cancer (CRC). Although typically associated with ten to a few hundred colonic adenomatous polyps, CRC develops in some individuals in the absence of polyposis. Serrated adenomas, hyperplastic/sessile serrated polyps, and mixed (hyperplastic and adenomatous) polyps can also occur. Duodenal adenomas are common, with an increased risk of duodenal cancer. The risk for malignancies of the ovary and bladder is also increased, and there is some evidence of an increased risk for breast and endometrial cancer. Additional reported features include thyroid nodules, benign adrenal lesions, jawbone cysts, and congenital hypertrophy of the retinal pigment epithelium.

Diagnosis/testing.

The diagnosis is established in a proband by identification of biallelic germline pathogenic variants in MUTYH on molecular genetic testing.

Management.

Treatment of manifestations: Suspicious polyps identified on colonoscopy should be removed until polypectomy alone cannot manage the large size and density of the polyps, at which point either subtotal colectomy or proctocolectomy is performed. Duodenal polyps showing dysplasia or villous changes should be excised during endoscopy. Abnormal findings on thyroid ultrasound examination should be evaluated by a thyroid specialist to determine what combination of monitoring, surgery, and/or fine needle aspiration is appropriate.

Surveillance: Colonoscopy with polypectomy every one to two years beginning at age 25-30 years; upper endoscopy and side viewing duodenoscopy every three months to four years beginning at age 30-35 years with subsequent follow up based on initial findings. Consider annual physical examination, thyroid ultrasound, and skin examination by a dermatologist.

Individuals with a heterozygous germline MUTYH pathogenic variant: offer average moderate-risk colorectal screening based on family history.

Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with MAP by molecular genetic testing for the MUTYH pathogenic variants identified in the proband in order to reduce morbidity and mortality in those who would benefit from appropriate surveillance beginning at age 10-15 years and early identification and treatment of polyps.

Genetic counseling.

MAP is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier with a small increased risk for CRC, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.

Suggestive Findings

MUTYH polyposis (MAP) should be suspected in an individual with the following clinical findings and family history [NCCN 2019].

Clinical findings

• A personal cumulative lifetime history of ten or more colorectal adenomas in an individual age ≤60 years
• A personal cumulative lifetime history of 20 or more colorectal adenomas in an individual of any age
• A personal cumulative lifetime history of any combination of 20 or more colorectal adenomas, hyperplastic polyps, and/or sessile serrated polyps (excluding rectal and sigmoid hyperplastic polyps)
• Sessile serrated polyposis syndrome:
  • At least five serrated polyps proximal to the sigmoid colon, of which two or more are >10 mm; OR
  • >20 serrated polyps of any size distributed throughout the colon (excluding hyperplastic polyps found in the rectum and sigmoid colon)
• Duodenal polyp(s) and/or duodenal cancer
• Colorectal cancer with or without a history of polyps and identification of a somatic KRAS pathogenic variant (c.34G>T in codon 12) or identification of specific mutational signature on tumor tissue testing due to a high percentage of somatic G>T transversions (e.g., COSMIC Signature 18; SigProfiler SBS18/SBS36; SignatureAnalyzer SBS18/SBS36) [Viel et al 2017].

Family history of colorectal cancer (± polyps) consistent with autosomal recessive inheritance.

Establishing the Diagnosis

The diagnosis of MAP is established in a proband by identification of germline biallelic pathogenic variants in MUTYH by molecular genetic testing (see Table 1 and Table 2).

Germline molecular genetic testing approaches can include gene-targeted testing (single-gene testing and/or multigene panel). Since the phenotype of MAP (as described in Suggestive Findings) overlaps with a number of other hereditary polyposis and colorectal cancer syndromes (see Differential Diagnosis), many individuals with MAP will likely be diagnosed using a multigene panel.

• Single-gene testing. Sequence analysis of MUTYH detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications (Table 1).
• A multigene panel that includes MUTYH and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Tumor tissue testing prior to germline molecular genetic testing of a proband is generally not required; however, it may be required in certain circumstances (e.g., by third-party payer policy). In other instances, review of past tumor testing on a proband may help determine the preferred germline molecular genetic testing approach (i.e., single-gene testing vs use of a multigene panel).

• Identification of a somatic KRAS pathogenic variant. The KRAS pathogenic variant (c.34G>T in codon 12), present in less than 5%-10% of sporadic colorectal cancers (CRCs), is found in 40%-100% of adenomas and 60%-90% of CRCs in persons with MAP [Nielsen et al 2011, Viel et al 2017]. Furthermore, 10%-25% of persons with CRCs with this somatic KRAS variant have biallelic germline MUTYH pathogenic variants.
  KRAS somatic molecular genetic testing is often routine in advanced CRCs to identify individuals who are eligible for MUTYH germline molecular genetic testing, including probands with atypical clinical findings (CRC and no or very few adenomas) [van Puijenbroek et al 2008, Guarinos et al 2014, Aimé et al 2015, Viel et al 2017].
• Microsatellite instability (MSI)-low (For information on MSI testing including advantages and disadvantages, click here). Although the majority of CRCs in persons with MAP are microsatellite stable, the MSI-high phenotype is found in a minority (0%-18%, mean: 4%) (see review in Nielsen et al [2011], Castillejo et al [2014]).

Clinical Description

MUTYH polyposis (MUTYH-associated polyposis; MAP) is characterized by a greatly increased lifetime risk for colorectal cancer (CRC) (43%-63% at age 60 years and a lifetime risk of 80%-90% in the absence of timely surveillance). The risk for malignancies of the duodenum, ovary, and bladder is also increased, and there is some evidence of an increased risk for breast and endometrial cancer (Table 3).

Colon polyps and cancer. Most individuals with MAP have between ten and a few hundred colonic polyps with a mean age of presentation of approximately 50 years. Persons with MAP can have colonic adenomas as well as serrated adenomas, hyperplastic/sessile serrated polyps, and mixed (hyperplastic and adenomatous) polyps [Sieber et al 2003, Chow et al 2006, Boparai et al 2008, O'Shea et al 2008]. Of note, eight of 17 persons with MAP had one or more hyperplastic colonic polyps and/or sessile serrated adenomas; findings in three of these eight individuals met criteria for the serrated polyposis syndrome (see Differential Diagnosis) [Boparai et al 2008]. A rectal clustering (studding) of a large number (i.e., >20) of hyperplastic polyps was found in ten of 16 persons with MAP [Church & Kravochuck 2016].

Molecular genetic testing of individuals with CRC has revealed that up to one third of persons with biallelic germline MUTYH pathogenic variants develop CRC in the absence of colonic polyposis [Croitoru et al 2004, Farrington et al 2005, Balaguer et al 2007, Cleary et al 2009, Pearlman et al 2017]. In a minority (0%-3.7%) of affected individuals, biallelic germline MUTYH pathogenic variants have been found in the index case of a family with a phenotype suggestive of Lynch syndrome [Nielsen et al 2011, Castillejo et al 2014].

In the absence of timely surveillance, the lifetime risk for CRC in individuals with MAP was between 80% and 90% [Lubbe et al 2009, Win et al 2014]. Colon cancers were found to be right-sided in 29%-69% of individuals with MAP [Lipton et al 2003, O'Shea et al 2008, Nielsen et al 2009a]. Metachronous or synchronous colon cancers occurred in 23%-27% of individuals with MAP [Lipton et al 2003, Nielsen et al 2009a].

In one report, survival of individuals with MUTYH CRC on average was better than survival in individuals with colorectal adenocarcinoma and unknown family history who did not have microsatellite instability testing [Nielsen et al 2010]. Five-year survival for persons with MAP CRC was 78% (which, after adjustment for differences in age, stage, sex, subsite, country, and year of diagnosis, remained better than for controls).

Duodenal polyps and cancer. Duodenal polyps occur in 17%-34% of individuals with MAP. The lifetime risk for duodenal cancer is approximately 4% [Nielsen et al 2006, Vogt et al 2009, Walton et al 2016].

Ovarian cancer. The incidence of ovarian cancer was significantly increased in women with MAP, with a lifetime risk of 6%-14% and median age at diagnosis of 51 years [Vogt et al 2009, Win et al 2016]. Biallelic germline MUTYH pathogenic variants were uncommon in a large cohort of women with ovarian cancer (1/7,646) [LaDuca et al 2020].

Bladder cancer. The incidence of bladder cancer was significantly increased, with a lifetime risk of 6%-8% for females and 6%-25% for males with MAP and a median age at diagnosis of 61 years (range 45-67) [Vogt et al 2009, Win et al 2016].

Other cancers

• Breast cancer. It is unclear if the risk for breast cancer is increased in women with MAP. The risk was found to be higher in one study, with median age at diagnosis 53 years (range 45-76) [Vogt et al 2009]. However, a second study did not find an increased breast cancer risk [Win et al 2016]. Although biallelic germline MUTYH pathogenic variants have not been reported in individuals from large breast cancer cohorts, one male with biallelic germline MUTYH pathogenic variants was reported in a cohort of 560 males with breast cancer [Rizzolo et al 2018].
• Endometrial cancer was diagnosed in two of 118 women with MAP, with a median age at diagnosis of 51 years and a lifetime risk of approximately 3% [Vogt et al 2009]. Sutcliffe et al [2019] reported endometrial cancer in four of 45 women with MAP.
• Gastric fundic gland polyps and gastric cancer. Among 150 individuals with MAP undergoing endoscopic surveillance, 17 (11%) had gastric fundic gland polyps. Although a higher risk for gastric cancer than in the general population was observed, the trend was not significant [Vogt et al 2009].
• Pancreatic cancer. Two (2%) of 83 individuals with MAP were diagnosed with pancreatic cancer [Sutcliffe et al 2019]. Two additional studies including 276 individuals with MAP did not report any instances of pancreatic cancer [Vogt et al 2009, Win et al 2016].
• Skin cancer. Thirteen of 276 individuals with MAP had a diagnosis of skin cancer including melanomas, squamous epithelial carcinomas, and basal cell cancers [Vogt et al 2009]. In this same cohort, five individuals also had sebaceous gland adenomas or sebaceous gland epitheliomas. Another study reported two melanomas and six other skin cancers in 81 individuals with MAP [Sutcliffe et al 2019].
• Thyroid cancer. Three of 24 individuals with MAP evaluated by thyroid ultrasound had papillary thyroid cancer [LaGuardia et al 2011]; a high incidence of thyroid cancer was not reported in other studies and may have reflected selection bias. Vogt et al [2009] reported two instances of thyroid cancer in 276 individuals with MAP.

Other extraintestinal findings in persons with MAP

• Thyroid nodules were identified in 16 of 24 individuals with MAP examined by ultrasound [LaGuardia et al 2011]. A second study reported thyroid nodules in two of 82 individuals with MAP [Sutcliffe et al 2019].
• Adrenal lesions (all benign and not hyperfunctioning) were identified in five (18%) of 21 of individuals with MAP in a prospective study [Kallenberg et al 2017].
• Dental abnormalities. Jawbone cysts were reported in 11 of 276 persons with MAP [Vogt et al 2009].
• Congenital hypertrophy of retinal pigment epithelium (CHRPE). The estimate of CHRPE in individuals with MAP is about 5.5%; however, this figure may also include misdiagnoses since pigment anomalies of the retina are quite frequent in the general population [Vogt et al 2009].

Genotype-Phenotype Correlations

Functional studies have shown differences in glycosylase activity between the c.536A>G pathogenic variant and the c.1187G>A pathogenic variant [Banda et al 2017]. Differences were also seen in clinical manifestations: homozygosity for c.536A>G was associated with a more severe phenotype and an approximately eight-year-earlier age of onset compared to homozygosity for c.1187G>A [Lubbe et al 2009, Nielsen et al 2009b, Terdiman 2009, Morak et al 2010].

For other common variants, such as p.Glu324His, which has up to a 50% minor allele frequency in some populations [Banda et al 2017], association with cancer risk has been reported; however, the reported risks are not consistent with mendelian inheritance and are not used to direct patient care.

Nomenclature

An outdated term for MUTYH polyposis is "autosomal recessive adenomatous polyposis."

The gene formerly designated MYH is now MUTYH.

Prevalence

It is estimated that 1%-2% of the general northern European, Australian, and US populations are heterozygous for a germline MUTYH pathogenic variant [Al-Tassan et al 2002, Cleary et al 2009, Win et al 2017]. The Genome Aggregation Database (gnomAD) reports a somewhat lower frequency of MUTYH pathogenic variants (~0.8%). Using these figures, the prevalence of 1:20,000 to 1:60,000 for persons with biallelic germline MUTYH pathogenic variants can be derived.

MAP is estimated to account for 0.7% of all CRC and between 0.5% and 6% of cohorts of familial or early-onset CRC in which affected individuals have a low number of adenomas (<15-20) [Sieber et al 2003, Cleary et al 2009, Lubbe et al 2009, Landon et al 2015, Pearlman et al 2017]. See also Table 4.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs of an individual diagnosed with MUTYH polyposis (MAP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

• Review of personal medical history with emphasis on those features related to MAP or colorectal cancer (CRC): colon polyps (majority are adenomas), rectal bleeding, abdominal pain and discomfort, bloating, diarrhea
• Colonoscopy and review of pathology
• Baseline upper endoscopy including visualization of the major ampulla starting at age 30-35 years
• Baseline thyroid ultrasound examination [LaGuardia et al 2011]
• Consider skin examination by a dermatologist.
• Consultation with a clinical geneticist and/or genetic counselor

Currently, investigations for other extracolonic manifestations of MAP are not recommended at the time of initial diagnosis.

Treatment of Manifestations

Practice parameters, including information on surgery, have been outlined by the following resources:

• National Comprehensive Cancer Network [NCCN 2019]
• American College of Gastroenterology [Syngal et al 2015] (full text)
• American Society of Colon and Rectal Surgeons [Church et al 2003]
• American Society of Clinical Oncology [Stoffel et al 2015] (full text)
• Society of Surgical Oncology [Guillem et al 2006] (full text)

Colon polyps and colon cancer. Surveillance guidelines for individuals with MUTYH polyposis are analogous to the guidelines for individuals with attenuated FAP. Colonoscopy and polypectomy is recommended every one to two years until polypectomy alone cannot manage the large size and density of the polyps, at which point colectomy may be necessary [Lipton & Tomlinson 2006, Sampson & Jones 2009]. Absolute indications for colectomy include documented or suspected CRC or significant symptoms (e.g., obstruction, bleeding), although these symptoms are uncommon in the absence of CRC. Relative indications for colectomy include presence of multiple adenomas >6 mm that cannot be reasonably managed by endoscopy, a significant increase in adenoma number between surveillance examinations, presence of adenomas with high-grade dysplasia, or inability to adequately survey the colon (e.g., due to innumerous diminutive adenomas or limited access to/compliance with colonoscopy) (see Surveillance).

Types of colectomy include the following:

• Proctocolectomy with ileal pouch anal anastomosis (IPAA), which can be performed laparoscopically, laparoscopically assisted, or open
• Total colectomy with ileorectal anastomosis (IRA)
• Total proctocolectomy with permanent ileostomy

The choice of procedure depends on the clinical circumstances.

• An IPAA is generally performed when the rectal polyp burden is high or as a second procedure after IRA when rectal disease burden cannot be managed endoscopically. The advantages of this procedure are near-elimination of risk for rectal cancer and relatively good preservation of bowel function. There may be an increased risk for bladder/sexual dysfunction and functional results can be variable.
• An IRA is generally considered when the rectal polyp burden is low and deemed to be endoscopically manageable. It is a technically straightforward procedure with low complication rates. It is usually associated with good functional outcome and minimizes risk for sexual or urinary dysfunction. This procedure should not be performed if there is severe rectal disease or the individual cannot reliably undergo endoscopic surveillance of the remaining rectum postoperatively.
• A total proctocolectomy with end ileostomy is almost never required unless a proctocolectomy is necessary (due to rectal polyp/cancer burden) and a contraindication to IPAA is present (e.g., a mesenteric desmoid preventing a pouch from reaching pelvic floor, low rectal cancer invading pelvic floor, or individual preference due to poor sphincter control).

Duodenal polyps. Management of polyps is similar to that in individuals with FAP. Endoscopic or surgical removal of duodenal and/or ampullary adenomas is recommended if polyps exhibit villous change or severe dysplasia, exceed 1 cm in diameter, or cause symptoms [Wallace & Phillips 1998, Saurin et al 1999, Kadmon et al 2001]. Surgical options include a pancreas-sparing duodenectomy, which is a good option when the papilla is not involved and there is no suspicion for cancer. Pancreaticoduodenectomy (Whipple procedure) is associated with significantly higher morbidity; however, it must be considered if the duodenal papilla is involved or cancer is identified or strongly suspected.

Abnormal thyroid findings should be evaluated by a thyroid specialist to determine the combination of monitoring, surgery, and/or fine needle aspiration that is appropriate [LaGuardia et al 2011].

Prevention of Primary Manifestations

For many individuals with MAP, colonic polyps are limited in number and surveillance with periodic colonoscopic polypectomy is sufficient to prevent CRC. Colonoscopy is therefore used for surveillance and prevention of CRC.

To reduce the risk for duodenal/periampullary adenocarcinoma, endoscopic or surgical removal of duodenal and/or ampullary adenomas should be considered if polyps exhibit villous change or severe dysplasia, exceed 1 cm in diameter, or cause symptoms.

Surveillance

Agents/Circumstances to Avoid

Currently, no studies have investigated external factors or lifestyle factors that could affect the severity of the manifestations of MUTYH polyposis.

Smoking may affect polyp development based on a case report of monozygotic twins with MAP in which a somewhat more severe phenotype was observed in the sister who smoked compared to her twin sister who did not smoke. While both twins had about 30 smaller low-grade adenomas, the twin sister who smoked also had three larger (6-10 mm) adenomas and one focal high-grade adenoma of 70 mm [Casper et al 2018].

Evaluation of Relatives at Risk

It is appropriate to clarify the genetic status of apparently asymptomatic older and younger sibs of an individual with MAP by molecular genetic testing for the MUTYH pathogenic variants identified in the proband in order to reduce morbidity and mortality in those who would benefit from appropriate surveillance (beginning at age 10-15 years) and early identification and treatment of polyps.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

MUTYH polyposis (MAP) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one MUTYH pathogenic variant).
• Heterozygous relatives of an individual with MAP are at a two- or at most threefold increased risk for late-onset colorectal cancer (CRC) (see Clinical Description, Heterozygotes; Evaluation of Relatives at Risk; and Surveillance, Individuals Heterozygous for a Germline MUTYH Pathogenic Variant).

Sibs of a proband

• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier.
• Heterozygous relatives of individuals with MAP are at a two- or, at most, threefold increased risk for late-onset CRC (see Clinical Description, Heterozygotes; Evaluation of Relatives at Risk; and Surveillance, Individuals Heterozygous for a Germline MUTYH Pathogenic Variant).

Offspring of a proband

• Unless the reproductive partner of a proband is heterozygous for a MUTYH pathogenic variant (i.e., a carrier), offspring will be obligate heterozygotes for a pathogenic variant in MUTYH.
• The carrier (heterozygote) frequency in the general northern European, Australian, and US population for a MUTYH pathogenic variant is 1%-2% (see Prevalence). Therefore, the risk to the offspring of an affected individual and a reproductive partner of northern European, Australian, or US origin of having MUTYH polyposis is 0.5%-1.0%.

Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of a MUTYH pathogenic variant.

Heterozygote Detection

Carrier testing for at-risk relatives requires prior identification of the MUTYH pathogenic variants in the family.

Reproductive partners of individuals with one or two MUTYH pathogenic variants can be offered MUTYH molecular genetic testing to determine MUTYH carrier status in order to clarify the risk for MAP in their offspring.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) and molecular genetic testing when this has not been done before, to young adults who are affected, are carriers, or at risk of being carriers and to their reproductive partner to determine the risk of MAP in offspring (see Carrier Detection).

Prenatal Testing and Preimplantation Genetic Testing

Once the MUTYH pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for MAP are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

DNA base excision repair plays a critical role in DNA damage repair caused by ionizing radiation, various chemical oxidants, and reactive oxygen species. In humans, the most mutagenic species from oxidative damage is 8-oxo7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), which tends to mispair with adenine instead of the usual cytosine. This leads to G:C>T:A transversions in the DNA [Isidro et al 2004].

The following enzymes work together in DNA base excision repair to prevent mutagenesis by DNA damage-produced 8-oxo-dG:

• 8-oxo-dGTPase (encoded by NUDT1): removes 8-oxo-dGTPs from the nucleotide pool to prevent incorporation into DNA
• N-glycosylase/DNA lyase (encoded by OGG1): detects and excises 8-oxo-dG adducts that have been misincorporated into DNA
• Adenine DNA glycosylase (encoded by MUTYH): recognizes and excises misincorporated adenine bases to prevent G:C>T:A transversions from occurring

Mechanism of disease causation. A lack of functional adenine DNA glycosylase leads to accumulation of G:C>T:A transversions in daughter DNA strands post replication. Studies indicate that this transversion is common in colorectal tumor DNA from individuals with MAP. These pathogenic variants result in loss of adenine DNA glycosylase function [Lipton & Tomlinson 2004].

MUTYH-specific laboratory technical considerations. MUTYH has multiple transcript variants encoding different isoforms (www.ncbi.nlm.nih.gov/gene/4595). The isoforms differ in their N-terminus, which contains a mitochondrial localization signal (MLS). The putative nuclear localization signals (NLS) are located at both the N-terminus and C-terminus. The functional significance of the MLS and NLS in MUTYH is not entirely clear. Possibly they possess different glycosylase activity levels and/or have different expression levels in different tissues [Ma et al 2004].

Following current HGVS recommendations, a DNA reference sequence (NM_001128425.1) that is the longest possible transcript was created. Reported nucleotide and amino acid variants after nucleotide position 157 (amino acid 53) may differ by up to 42 nucleotides (14 amino acids). Care must be taken when searching the published literature for reported variants.

Cancer and Benign Tumors

In general, MAP carcinomas somewhat mimic Lynch and sporadic mismatch repair (MMR)-deficient tumors with a frequently proximal location in the colon and a high number of tumor-infiltrating lymphocytes (TILs) [Nielsen et al 2009a]. Loss of HLA class I expression, a common event in Lynch tumors, was also found to be a frequent event in MAP carcinomas [de Miranda et al 2009]. Also comparable to Lynch tumors, the majority of MAP carcinomas appear near-diploid, and chromosome regions of copy-neutral loss of heterozygosity are frequent [Lipton et al 2003, Middeldorp et al 2008].

Recent studies performed whole-exome sequencing in MAP carcinomas and adenomas [Weren et al 2015, Rashid et al 2016, Viel et al 2017]. In general, the combination of the excess G:C>T:A transversion and specific sequence context (transversions occurring preferentially in AGAA or TGAA motifs) led to assigning a novel mutational signature for MAP tumors, termed signature 36 [Viel et al 2017].

The overall mutation rate in MAP carcinomas was estimated at approximately twofold higher than in microsatellite-stable (MSS) carcinomas – in contrast to MSI CRCs, which are characterized by an almost tenfold increase over MSS carcinomas [Viel et al 2017]. A higher mutation load when comparing MAP with FAP tumors was found in adenomas from colon and duodenum as well [Rashid et al 2016, Hurley et al 2018]. The higher somatic mutation load in MAP tumors could cause a more activated immune system, comparable to that in Lynch/MMR-deficient colorectal tumors, and also indicates that tumors may be sensitive for immune therapies such as PD-1 blockade [Le et al 2015]. However, no such clinical research has been performed in individuals with MAP. Vaccine strategies now being developed could also be effective in MAP, but this also requires further research.

Acknowledgments

The authors of this manuscript would like to thank Beth Dudley, MS, MPH, CGC for her assistance in editing and providing feedback about this GeneReview.

Author History

Randall Brand, MD (2012-present)
Elena Infante, MS, CGC (2012-present)
Henry Lynch, MD; Creighton University (2012-2019)
Maartje Nielsen, MD (2012-present)

Revision History

• 27 May 2021 (mn) Revision: variant removed from Table 7: c.1118C>T
• 10 October 2019 (sw) Comprehensive update posted live
• 24 September 2015 (me) Comprehensive update posted live
• 4 October 2012 (me) Review posted live
• 21 June 2011 (ei) Original submission

Published Guidelines / Consensus Statements

• NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™). Colorectal cancer screening. National Comprehensive Cancer Network, Inc. 2019.

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