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. 2024 Aug;91(2):265-272.
doi: 10.1016/j.jaad.2023.11.070. Epub 2024 Mar 20.

Germline cancer susceptibility in individuals with melanoma

Pauline Funchain  1 , Ying Ni  2 , Brandie Heald  3 , Brandon Bungo  4 , Michelle Arbesman  5 , Tapas R Behera  6 , Shelley McCormick  7 , Jung Min Song  8 , Lucy Boyce Kennedy  5 , Sarah M Nielsen  9 , Edward D Esplin  9 , Emily Nizialek  10 , Jennifer Ko  11 , Claudia M Diaz-Montero  2 , Brian Gastman  12 , Alexander J Stratigos  13 , Mykyta Artomov  14 , Hensin Tsao  15 , Joshua Arbesman  12
Affiliations

Germline cancer susceptibility in individuals with melanoma

Pauline Funchain et al. J Am Acad Dermatol. 2024 Aug.

Abstract

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%.

Keywords: DNA repair; cancer predisposition; familial melanoma; family history; genetic testing; germline; homologous repair deficiency; inherited cancer syndromes; melanoma.

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Conflict of interest statement

Conflicts of interest Dr Funchain serves on the advisory committee for Eisai, Novartis, Bristol-Myers Squibb, and Merck; and serves as a consultant for GigaGen and Nirvana Healthcare Ventures. Authors Heald and Nielsen and Dr Esplin are employees and shareholders of Invitae. Dr Gastman serves on the advisory committee for Merck and Castle Biosciences. Arbesman serves on the advisory committee for Castle Biosciences. Dr Ni, Dr Bungo, Arbesman, Dr Behera, Author McCormick, Author Song, Author Kennedy, Dr Nizialek, Dr Ko, Author Diaz-Montero, Dr Stratigos, Dr Artomov, and Dr Tsao have no conflicts of interest to declare. Research support to institution from Pfizer, Bristol-Myers Squibb, and Taiho Oncology (Dr Funchain). Research support to institution from Castle Biosciences and Variant Bio (J. Arbesman).