Melanoma: Genetics and Risk Factors

Dysplastic nevus syndrome (aka, familial atypical multiple mole-melanoma [FAMMM] or B-K mole syndromes) 26892650

• Familial melanoma syndrome is characterized by multiple and early onset melanomas (33-45 years of age) and increased risk of pancreatic cancer and neural system tumors (melanoma-astrocytoma syndrome).  It is caused by germline mutation in CDKN2A, a gene that encodes for p16 and p14ARF tumor suppressors, and is inherited in an autosomal dominant fashion.  They are intranuclear proteins downstream of the MAPK pathway, and affect transcription.

  • p16 variant a/w pancreatic ca., p14ARF w/ neural tumors (B1993).

  • Less commonly, a/w CDK4 mutations. CDK4 encodes a protein that complexes with cyclin D and is inhibited by p16.  The phenotype is the same regardless if the mutation ins CKDN2A or CDK4.

• ​~1% of patients with a single primary melanoma will have a germline CDKN2A mutation.

• ~3% of patients with multiple primary melanomas will have a germline CDKN2A mutation.

• Patients with CDKN2A mutations are more likely to have early onset melanomas and a family history of melanoma.

Diagnostic criteria

1. Melanoma in at least 1 first or second degree relative.

2. At least 50 nevi, many of which are atypical: variegated tan, brown, or pink coloration; macular with papular center; >6mm; indistinct and irregular borders.

3. Specific histologic features: asymmetry, subepidermal fibroplasia, lentiginous melanocytic hyperplasia with spindle or epithe- lioid melanocytes, variable dermal lymphocyte infiltration, presence of ‘‘shouldering’’.

Management

• TBSE q3-6 months with special attention to clinically atypical nevi. Consider total body photography.

• Children of families with FAMMM should have TBSE starting in late adolescence.

• Consider genetic testing. Algorithm for considering genetic testing found here: 26892650

• Referral for appropriate screening considering possible increased risk of pancreatic cancer.

BAP1 Tumor Predisposition Syndrome​

• Increased rates of onychopapillomas and other nail findings. 38759225

Germline Single Nucleotide Variants​ (SNVs) 39141363

• Shared Genetics but Some Differences: Both in situ and invasive melanomas share significant genetic similarities in SNVs.

  • Loci near IRF4, KLF4, and HULC are more strongly linked to in situ melanoma.

  • Loci near MC1R are more influential in invasive melanoma.

• Heritability estimates (percent of risk of melanoma attributable to genetics) were 6.7% for in situ and 4.9% for invasive melanoma.

• Polygenic Risk Scores (PRS): Researchers developed genetic risk scores that could potentially help predict whether an individual is at higher risk for invasive melanoma rather than in situ melanoma.