Introduction

Familial atypical multiple mole melanoma (FAMMM) syndrome is an autosomal dominant genodermatosis characterized by multiple melanocytic nevi, usually more than 50, and a family history of melanoma (Figure 1 and Figure 2). It is associated with mutations in the CDKN2A gene and shows reduced penetrance and variable expressivity. Some FAMMM kindreds show an increased risk for the development of pancreatic cancer and possibly other malignancies (1-6).

Pathology

The histopathologic characteristics of melanoma in FAMMM kindreds are not different from those seen in sporadic cases of melanoma and, thus, are not useful in diagnosing the syndrome. Superficial spreading melanoma (SSM) and nodular melanoma are the most frequently encountered histological melanoma subtypes in patients with CDKN2A mutations, which is consistent with the relative early age of onset. Some studies have shown a predominance of SSM in FAMMM patients compared to sporadic melanoma controls, while other studies have shown no difference between these groups.[20]

In 2002, Masback and others examined the clinical and histopathologic characteristics of cutaneous malignant melanomas in 26 individuals from nine CDKN2A mutation-positive families and compared them with cutaneous malignant melanomas from 78 age-matched controls and with cutaneous malignant melanomas from a 667-member population-based group (18). For each group, they evaluated Breslow thickness, Clark invasion level, ulceration, inflammation, regression reaction and the presence of benign dermal nevus cells. The differences seen in Breslow thickness between the groups did not reach statistical significance, which has been corroborated by some studies (19-21) and challenged by others (22-24). When comparing Clark invasion level, CDKN2A mutation cases were significantly less invasive (Clark level II versus levels III and IV) than the age-matched controls and population-based lesions. None of the histopathologic differences, however, were sufficient to establish a diagnosis between a CDKN2A-associated melanoma from a non-CDKN2A melanoma.

The Gene—CDKN2A

The CDKN2A gene is located on chromosome 9p21.3. Two main transcripts, isoforms ‘1’ and ‘4’, each contain three exons and span 7288 and 26740 bp, respectively. They encode proteins of 156 and 173 amino acids; isoform ‘1’ encodes p16(INK4a), while isoform ‘4’ encodes p14(ARF), a protein that is structurally unrelated to p16(INK4) but acts in cell cycle G1 control by stabilizing the tumor suppressor protein p53.

The first exons for p16(INK4) and p14(ARF) are coded independently. The second exons begin with the same coding sequence (Figure 3). However, they have different reading frames and thus encode different amino acid sequences. Therefore, despite having the same coding sequence for exon 2, the proteins do not have a similar amino acid sequence.

The only significant evolutionary conservation in CDKN2A is observed in exon 2, where a multispecies sequence alignment shows 76% sequence identity and 94% sequence similarity across six mammalian species (Figure 4). While exon 2 of both alternative reading frames overlaps, the drop in conservation beyond the coding region of isoform 4 (Figure 5) suggests that this isoform is more responsible for the observed conservation.

Table 3 shows the prevalence of somatic and germline CDKN2A mutations.

Table

Table 3. Prevalence of CDKN2A mutations in different populations.

The Protein—P16(INK4a), P15(INK4b), P18(INK4c)

Germline mutations of the CDKN2A gene seen in melanoma and pancreatic cancer-prone families are typically missense or nonsense mutations that impair the inhibitor function of proteins p16(INK4), p15(INK4b), or p18(INK4c). These proteins normally act at the G1/S checkpoint in the cell cycle, where they inhibit the cyclin-dependent kinases CDK4 and CDK6, thus preventing phosphorylation of the retinoblastoma protein RB1. This inhibits the release of transcription factors that would ordinarily induce S phase progression. Thus when mutations in the CDKN2A gene disrupt the function of p16(INK4), there is improper progression from the G1 to the S phase, allowing continued, uncontrolled cell proliferation (1, 7).

And while mutations involving p16(INK4) may be present in only a portion of FAMMM kindreds, p16(INK4) is somatically inactivated in 95% of sporadic cases of pancreatic cancer (1) and 40% of familial melanoma (7).

Diagnosis

Clinical Evaluation

FAMMM is a clinical diagnosis based on numerous nevi, including atypical nevi with ABCDE (see below) characteristics resembling early melanoma, and a family history of melanoma. The diagnostic criteria for FAMMM syndrome can be seen in Table 1, as outlined by both the National Cancer Institute and the National Institutes of Health consensus paper (25, 26). An integral aspect of the diagnosis is a comprehensive cancer family history (27).

Table

Table 1. Diagnostic criteria for Familial Atypical Multiple Mole Melanoma syndrome

The clinical and histopathologic characteristics of melanoma in FAMMM kindreds are not significantly different from those seen in sporadic cases of melanoma and, thus, are not useful in diagnosing the syndrome (See Pathology). Currently, most pigmented nevi are evaluated for melanoma on the basis of the subjective ABCDE characteristics of the nevus, referring to asymmetric shape, border irregularity, color variegation, diameter greater than 6 mm, and elevation or evolution (28). Other, more objective methods of evaluation have been employed to reduce diagnostic errors, including dermatoscopy, photography, digital dermatoscopy, and computer image analysis (29).

CDKN2A mutations and melanoma

A recent review of 466 melanoma multiplex families (2137 patients) revealed 38% had CDKN2A mutations, though the frequency varied significantly by geography. Boston, Emilia-Romagna, Philadelphia, Brisbane, Tel Aviv, and Sydney all had CDKN2A mutation frequency of <25%, whereas Genoa, Glasgow, Leeds, Leiden, Lund, and Toronto displayed a mutation frequency of >50%. Genoa, Leiden, and Toronto all had mutation frequencies of close to 70%. One-hundred seventy-eight families had CDKN2A germline mutations involving p16(INK4) and within those families, 57 different CDKN2A mutations were detected. Thirty-five percent of the mutations were observed in more than one family. The CDKN2A mutation distribution was 65% missense, 16% deletions, 7% insertions or duplications, and splicing and nonsense mutations each accounted for 5%. Australia and United Kingdom shared the same most common mutations, as did France with Mediterranean Europe. The largest number of different mutations was seen in North America, consistent with its mixed ancestry (7).

There is limited data on CDKN2A mutations in sporadic melanoma cases. Reported studies have shown a low CDKN2A mutation rate in sporadic melanoma tumors. In one study of 48 sporadic melanomas, 2% had a point mutation and only 20% had a deletion in the CDKN2A gene (30). Another study of sporadic melanomas revealed loss of heterozygosity in 24% and homozygous deletion in 15% (31). The results of these studies suggest that loss of the CDKN2A is not likely involved in the initial formation of cutaneous malignant melanoma.

CDKN2A mutations and pancreatic cancer

There is no significant data on germline CDKN2A mutations in sporadic pancreatic cancer cases. They are assumed to be rare. Studies have shown p16(INK4a) inactivation in 95% of sporadic pancreatic cancers (1).

A study of the world’s largest familial melanoma database documented an association between pancreatic cancer and CDKN2A mutations in melanoma multiplex families (7). Twenty- eight percent of CDKN2A mutation-positive kindreds had a pancreatic cancer compared to 6% of CDKN2A mutation-negative kindreds. Seventy-four percent of families with pancreatic cancer harbored a CDKN2A mutation compared to 33% of those families with melanoma only (7). One study estimated penetrance for pancreatic cancer to be 17% in CDKN2A mutation carriers by 75 years of age (6).

The frequency of pancreatic cancer in CDKN2A mutation-positive families varied from <11% to >60% depending on the specific mutation involved. Sixty-six percent of CDKN2A mutation kindreds harbor one of the ten most common CDKN2A mutations, and pancreatic cancer frequency was evaluated for each of these ten common mutations. For mutations p.R112_L113insR and c.225_24del19 the pancreatic cancer frequency was >60% while it was 35% to 50% in p.L32P, p.V126D, and p.G101W, 15% to 25% in p.R24P and c.-34G>T, and <11% in p.M53I, c.IVS2-105A>G and c.32_33ins9-32.

Numerous other studies have documented the association between CDKN2A mutations and pancreatic cancer (1, 2, 6, 11, 32). In 1990, Bergman and others examined 200 family members from 9 well-documented FAMMM kindreds and found a significantly higher than expected incidence of pancreatic cancer (2). An increased risk of pancreatic cancer in melanoma-prone families with a known CDKN2A mutation has also been documented. (13–22—fold increase) (32). A study of 19 families with known CDKN2A mutations revealed an increased risk of pancreatic cancer and an estimated cumulative risk of developing pancreatic cancer by age 75 years of 17%(6). In 2002, Bartsch and others showed a correlation between CDKN2A germline mutations and pancreatic cancer by examining CDKN2A prevalence in pancreatic cancer-only families and in families with both pancreatic cancer and melanoma. None of the 18 pancreatic cancer-only families had CDKN2A mutations, compared to 2 of the 5 pancreatic cancer and melanoma families (1). In addition, a pedigree analysis performed on a familial melanoma kindred with known CDKN2A mutations found an observed-expected ratio of 8.9 to 12.6 for pancreatic cancer (11).

Numerous studies have verified a correlation between CDKN2A gene mutations and FAMMM syndrome, yet others illustrate the limitations of our understanding of this relationship. In 2000, Goldstein and others studied 104 melanoma patients from 17 CDKN2A kindreds and found that only six of these 17 families expressed pancreatic cancer. The specific CDKN2A mutations were determined and the same mutations were seen in families with and without pancreatic cancer (8). Gruis and others studied 7 FAMMM kindreds in 1995 with similar results (33). Six of the families harbored the same 19 base pair deletion yet between three of those families, there were five cases in which individuals expressed melanoma and other FAMMM characteristics without expressing the deletion in their genotype. Another study of eight CDKN2A kindreds revealed great diversity between and within families (4). In some families, melanoma was the predominant malignancy while, in others, pancreatic cancer predominated the cancer presentation. Some families trended toward early onset of pancreatic carcinoma while others displayed later onset. Several CDKN2A mutation positive individuals from different families did not express any of the classic FAMMM phenotype characteristics.

CDKN2A mutations and other cancers

A number of studies have addressed the concern for increased susceptibility to cancers other than pancreatic cancer in melanoma-prone, CDKN2A mutation-positive kindreds. In 1981, Lynch and others noted carcinoma of the lung, skin, larynx, and breast, as well as primary intraocular melanoma in a single FAMMM kindred in higher than expected frequencies. However, given the small size of this report, no significant patterns could be established (34). In 1983, Lynch and others documented a five-fold increase in risk of cancer at all anatomic sites in an analysis of 80 FAMMM patients, but were unable to show significance in any specific organ cancer due to study size (5). The findings of this study have been challenged (35) on the grounds of selection bias as the participants were chosen from a study of hereditary cancer syndromes.

Follow-up studies have been mixed on the risk of non-melanoma, non-pancreatic cancer in CDKN2A mutation carriers. Greene and others, in 1987, studied 14 FAMMM kindreds and found no “striking diathesis” for non-melanoma cancers in these families (35). Another study of 200 FAMMM patients revealed an excess of digestive system cancer, particularly pancreatic cancer in 9 FAMMM kindreds, but revealed no significantly increased risk for the other cancers tested, including breast and respiratory system cancer (2). A review of 19 FAMMM kindreds with a known p16 mutation found a relatively high number of lung cancer cases (6). In 2002, Bartsch and others studied 18 familial pancreatic cancer, CDKN2A/p16-mutation kindreds without a history of melanoma and 5 families with the p16 mutation and both pancreatic cancer and melanoma (1). Other tumors documented during this study were breast, prostate, lung, esophagus, stomach, and colon cancer. Eight other FAMMM kindreds studied experienced additional primaries of the lung, breast, esophagus, and endometrium, as well as sarcoma, which may represent other malignancies associated with CDKN2A mutations (4). In 2000, Borg and others also noted an increased frequency of breast cancer in CDKN2A mutation melanoma prone families (3). Table 2 shows a list of other malignancies documented in FAMMM kindreds.

Table

Table 2. Malignancies other than pancreatic cancer and melanoma reported in FAMMM kindreds

An additional study evaluated the role of CDKN2A mutations in early-onset cancers of the breast, pancreas, and malignant melanoma. The study of 189 patients revealed infrequent alterations in the CDKN2A gene, suggesting that CDKN2A gene mutations do not play a significant role in the development of these early-onset malignancies (36).

Penetrance, expressivity, and modifiers

The penetrance for melanoma in kindreds with CDKN2A mutations is estimated at 58% to 92% by 80 years of age and varies with geography (11). The penetrance in CDKN2A mutation carriers for pancreatic cancer has been estimated to be 17% by 75 years of age (6). As noted above, there is wide variation in published estimates of the penetrance of CDKN2A mutations.

The single most important modifier in the risk of pancreatic cancer appears to be cigarette smoking. Smoking increases the risk of pancreatic cancer in the general population 1.5 to 5.5-fold (37). In 2003, Rulyak and others studied pancreatic cancer-prone families and noted that pancreatic cancer developed approximately 10 years earlier in smokers as compared to nonsmokers (38).

Natural History

Screening and Management

Melanoma and pancreatic cancer cause significant morbidity and mortality in FAMMM patients. The authors support the view that all FAMMM patients be counseled on screening. Given the lack of convincing and concordant data regarding CDKN2A mutation status and cancer risk, CDKN2A mutation should not be used for risk stratification or determination of follow-up program at this time (47).

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