Germline cancer susceptibility in individuals with melanoma

Background: Prior studies have estimated a small number of individuals with melanoma (2%-2.5%) have germline cancer predisposition, yet a recent twin study suggested melanoma has the highest hereditability among cancers. Objective: To determine the incidence of hereditary melanoma and characterize the spectrum of cancer predisposition genes that may increase the risk of melanoma. Methods: Four hundred individuals with melanoma and personal or family history of cancers underwent germline testing of >80 cancer predisposition genes. Comparative analysis of germline data was performed on 3 additional oncologic and dermatologic data sets. Results: Germline pathogenic/likely pathogenic (P/LP) variants were identified in 15.3% (61) individuals with melanoma. Most variants (41, 67%) involved genes considered unrelated to melanoma (BLM, BRIP1, CHEK2, MLH1, MSH2, PMS2, RAD51C). A third (20, 33%) were in genes previously associated with familial melanoma (BAP1, BRCA2, CDKN2A, MITF, TP53). Nearly half (30, 46.9%) of P/LP variants were in homologous repair deficiency genes. Validation cohorts demonstrated P/LP rates of 10.6% from an unselected oncologic cohort, 15.8% from a selected commercial testing cohort, and 14.5% from a highly selected dermatologic study. Limitations: Cohorts with varying degrees of selection, some retrospective. Conclusion: Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.