CDKN2A – Familial Atypical Multiple Mole Melanoma Syndrome

Familial atypical multiple mole melanoma (FAMMM) syndrome is an autosomal dominant cancer predisposition disorder characterised by multiple dysplastic naevi, cutaneous melanoma and an elevated risk for pancreatic carcinoma, nerve sheath tumours, brain neoplasms and soft tissue sarcomas (HP:0002861, HP:0030692, HP:0030448). Germline mutations in CDKN2A (encoding p16^INK4a and p14^ARF) underlie the majority of FAMMM cases and result in loss of both cell-cycle and p53 pathway control (PMID:26876133).

Autosomal dominant inheritance of CDKN2A mutations was first confirmed by linkage and haplotype analysis in seven Dutch families, establishing CDKN2A as the melanoma susceptibility locus on 9p21 (PMID:7640518). A recurrent 19-bp founder deletion (c.268_286del (p.Arg90fs)) segregates with melanoma in these families, with complete co-segregation in affected relatives (PMID:7640518).

Subsequent multi-center studies of 10 extended FAMMM kindreds (n=1,085 individuals) demonstrated that CDKN2A mutation carriers develop melanoma and related malignancies at a significantly younger age than noncarriers, with early-onset cancers observed across diverse tumour types (PMID:30967399).

The CDKN2A variant spectrum includes missense substitutions, splice-site changes (e.g., c.194-1G>C), small indels and large intragenic deletions. The prototypic c.268_286del (p.Arg90fs) frameshift mutation results in loss of the ankyrin repeat domain essential for CDK4 binding and cell-cycle inhibition (PMID:7640518).

Functional assays — including site-directed mutagenesis, yeast two-hybrid and in vitro kinase tests — show that p16^INK4a mutants fail to inhibit CDK4/6, while murine models combining Ink4a deficiency with oncogenic Ras develop melanomas with high penetrance and loss of the wild-type allele (PMID:7780957; PMID:9353252). These data support haploinsufficiency of both p16^INK4a and p14^ARF as the primary pathogenic mechanism.

Genetic modifiers, such as MC1R R151C, further increase melanoma risk in p16-Leiden carriers, explaining variable penetrance and phenotypic expressivity (PMID:11500806).

Collectively, >25 unrelated families with robust linkage, segregation and functional data define a Definitive gene-disease relationship between CDKN2A and FAMMM syndrome. Ongoing modifier and management studies continue to refine clinical surveillance. Key take-home: CDKN2A testing is essential for at-risk individuals with dysplastic naevi or familial melanoma history to guide targeted cancer surveillance.

References

• Melanoma research • 1995 • CDKN2 explains part of the clinical phenotype in Dutch familial atypical multiple-mole melanoma (FAMMM) syndrome families. PMID:7640518
• Cancer research • 2019 • Analysis of the CDKN2A Gene in FAMMM Syndrome Families Reveals Early Age of Onset for Additional Syndromic Cancers. PMID:30967399
• British Journal of Dermatology • 2016 • CDKN2A mutations with p14 loss predisposing to multiple nerve sheath tumours, melanoma, dysplastic naevi and internal malignancies: a case series and review of the literature. PMID:26876133
• Cancer research • 1995 • Mutational effects on the p16INK4a tumor suppressor protein. PMID:7780957
• Genes & Development • 1997 • Cooperative effects of INK4a and ras in melanoma susceptibility in vivo. PMID:9353252
• American Journal of Human Genetics • 2001 • Melanocortin-1 receptor variant R151C modifies melanoma risk in Dutch families with melanoma. PMID:11500806

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