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A 35-year-old patient presents with a newly diagnosed melanoma on the upper back. Physical exam reveals more than 50 dysplastic nevi. Family history is significant for melanoma in his father (age 40), paternal uncle (age 45), and paternal grandmother (age 55), with his paternal uncle also diagnosed with pancreatic cancer at age 62. Genetic testing identifies a pathogenic variant in CDKN2A.
AD; CDKN2A (9p21.3)
- Encodes two distinct tumor suppressor proteins via alternative reading frames:
- p16(INK4a): inhibits CDK4/6, preventing Rb phosphorylation and blocking G1-to-S cell cycle progression
- p14(ARF): stabilizes p53 by inhibiting MDM2-mediated degradation
- Loss of both tumor suppressors from a single gene contributes to high cancer risk
- Variable penetrance influenced by UV exposure, geographic latitude, and genetic modifiers
- Familial atypical multiple mole melanoma syndrome (FAMMM)
- Multiple dysplastic nevi (typically >50)
- Melanoma risk: 60-90% by age 80
- Pancreatic cancer risk: 15-25% lifetime
- Variable penetrance (higher in populations with greater UV exposure)
- May also modestly increase risk of other cancers (breast, lung, head and neck)
- Multiple primary melanomas are common
- Clinical criteria: three or more melanomas in the family (across first- and second-degree relatives), or two or more primary melanomas in one individual
- Genetic testing for CDKN2A pathogenic variants (multi-gene panel or targeted)
- CDK4 testing may be considered if CDKN2A is negative and clinical suspicion is high
- Full-body skin exams every 6 months by a dermatologist experienced in dermoscopy
- Monthly patient self-skin exams with total body photography as a baseline
- Strict sun protection (sunscreen, protective clothing, UV avoidance)
- Pancreatic cancer screening if family history of pancreatic cancer: EUS or MRCP starting at age 40, or 10 years before the youngest pancreatic cancer diagnosis in the family
- Cascade testing recommended for at-risk relatives
- No consensus on screening for other associated cancers at this time
"sKiN in cdKN": CDKN2A = skin cancer (melanoma). FAMMM is the melanoma-pancreatic cancer syndrome (M-PCS).
FAMMM criteria: Two or three close relatives diagnosed with melanoma and/or pancreatic cancer, or a family member diagnosed with melanoma multiple times. Some affected individuals have 50 or more moles.