Prevalence of Familial Melanoma Genes and Cancer Risk Among Genomically Ascertained Individuals
Alisa M Goldstein1, Jung Kim1, Jeremy S Haley2
1Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Rockville, Maryland.
JAMA Dermatology
|May 27, 2026
Summary
This study found that pathogenic variants in familial melanoma genes are more common than previously thought, especially in individuals with early-onset melanoma. These findings may lead to updated genetic testing guidelines for cancer risk.
Area of Science:
- Genetics and Genomics
- Oncology
- Population Health
Background:
- Previous studies on germline pathogenic variants in familial melanoma genes often involved individuals with a personal or family history of cancer, potentially leading to ascertainment bias.
- Understanding the prevalence of these variants in the general population is crucial for accurate risk assessment and genetic counseling.
Purpose of the Study:
- To estimate the prevalence of pathogenic variants in key familial melanoma genes within large, genomically ascertained cohorts.
- To investigate the association between these variants and various cancer risks, including melanoma and other malignancies.
Main Methods:
- A genome-first analysis was conducted on two population-scale cohorts: the UK Biobank (UKBB) and Geisinger MyCode (GMC).
- Data included germline pathogenic variant status in eight familial melanoma genes (ACD, BAP1, CDKN2A, CDK4, MITF E318K, POT1, TERF2IP, TERT promoter) and linked cancer registry data.
- Statistical analyses adjusted for demographic and lifestyle factors to assess cancer odds ratios and time-to-cancer associations.
Main Results:
- The combined prevalence of pathogenic variants across the evaluated genes ranged from 0.5% to 0.9% in the UKBB and GMC cohorts.
- Prevalence exceeded 2.5% in individuals with multiple or early-onset cutaneous melanoma, suggesting a threshold for germline testing.
- Established gene-cancer associations were replicated, and novel associations were identified for BAP1, CDKN2A, MITF E318K, and POT1 with various cancers. Individuals with CDKN2A or MITF E318K variants developed melanoma at younger ages.
Conclusions:
- The prevalence of pathogenic variants in familial melanoma genes is significant in the general population, necessitating a re-evaluation of current germline testing guidelines.
- The identified gene-cancer associations suggest a broader spectrum of cancer risk for several genes than previously recognized.
- These findings have implications for refining cancer risk counseling and informing personalized cancer prevention strategies.
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