Familial adenomatous polyposis (FAP) / MUTYH-associated polyposis (MAP)

FAMMM predisposes to cutaneous melanoma, pancreatic adenocarcinoma, and selected central nervous system tumours. The CNS spectrum, including glioma, astrocytoma, and glioblastoma multiforme, is reported predominantly with variants disrupting p14ARF, one of the two protein isoforms. Cutaneous melanoma is the most commonly associated malignancy; affected individuals frequently develop multiple primary melanomas over a lifetime. Pancreatic adenocarcinoma is the second most common malignancy and typically presents at a mean age between 65 and 71 years. Many affected individuals display a high total nevus count (often more than 50) with atypical-appearing nevi, though both the number and morphology of nevi vary considerably. Superficial spreading and nodular subtypes appear more prevalent than in sporadic melanoma, and clinical expressivity is highly variable between and within families, shaped in part by ultraviolet exposure and tobacco use.

Due to insufficient data, no reliable statement on prevalence can currently be made. Among individuals with multiple primary melanomas, approximately 5% of those without a family history and approximately 10% of those with three or more affected relatives carry a germline CDKN2A pathogenic variant.

FAMMM is caused by germline pathogenic variants in CDKN2A on 9p21.3. CDKN2A is a tumour suppressor gene encoding two distinct proteins, p16INK4a and p14ARF, through alternative first exons sharing a common second exon. p16INK4a inhibits cyclin-dependent kinases CDK4 and CDK6, supporting RB-mediated cell-cycle arrest, while p14ARF inhibits MDM2 and thereby stabilises TP53. Loss-of-function variants affecting either or both isoforms abolish these growth-suppressive signals, predisposing melanocytes, pancreatic ductal cells, and selected nervous-system precursors to malignant transformation.