Prevalence of Familial Melanoma Genes and Cancer Risk Among Genomically Ascertained Individuals

作者：Alisa M. Goldstein, Jung Kim, Jeremy S. Haley, Jiang Li, Diane T. Smelser, H. Shanker Rao, Jessica N. Hatton, Xiaohong R. Yang, Kevin Brown, Margaret A. Tucker, Elizabeth G. Berry, Andrew Waters, DJ Adams, W. Marston Linehan, John M. Kirkwood, Peter A. Kanetsky, David J. Carey, Douglas R. Stewart, Michael R. Sargen · 发表于：JAMA Dermatology · 年份：2026 · DOI：10.1001/jamadermatol.2026.1305 · 被引用次数：2 · 研究领域：Cutaneous Melanoma Detection and Management、Melanoma and MAPK Pathways、BRCA gene mutations in cancer

Importance: The prevalence of germline pathogenic variants in familial melanoma genes has primarily been studied in individuals with a personal or family history of cancer, an approach that may introduce ascertainment bias. Objective: To estimate the prevalence of pathogenic variants in clinically actionable familial melanoma genes and their associated cancer risks. Design, Settings, and Participants: This was a genome-first analysis of 2 population-scale genomically ascertained cohorts of individuals registered in the UK Biobank (UKBB) and the US Geisinger MyCode (GMC) databases, each linked with institutional (GMC) or national (UKBB) cancer registry data from 1970 through 2024. Data analyses were conducted from January 2025 through January 2026. Exposures: Germline pathogenic variant status in familial melanoma genes. Main Outcomes and Measures: Prevalence of pathogenic variants in 8 major familial melanoma genes: ACD, BAP1, CDKN2A, CDK4, MITF E318K, POT1, TERF2IP, and TERT promoter; and associated cancer risks among individuals in the UK and US who had been genomically ascertained. Cancer odds ratios and time to cancer analyses were adjusted for sex, birth year, body mass index, and smoking status. Results: The analysis included a total of 696 665 individuals who were genomically ascertained, 227 286 (mean [SD] age, 57.7 [19.6] years) from GMC and 469 379 (mean [SD] age, 70.0 [8.0] years) from UKBB. The cohorts were predominantly female (GMC, 60.6%; UKBB, 54.2%), and of Eu...