A LARGE population-based genomic study has found that pathogenic variants in familial melanoma genes are more common than previously recognised and may be associated with a broader spectrum of cancers than current clinical guidance reflects.
The study analysed 696,665 genomically characterised individuals from the UK Biobank and the US Geisinger MyCode cohorts. Researchers evaluated pathogenic variants in eight established familial melanoma genes: ACD, BAP1, CDKN2A, CDK4, MITF E318K, POT1, TERF2IP, and the TERT promoter.
Familial Melanoma Genes More Prevalent Than Expected
The investigators reported that the combined prevalence of pathogenic variants ranged from 0.5% in the Geisinger cohort to 0.9% in UK Biobank participants. Among individuals with multiple cutaneous melanomas or melanoma diagnosed before age 40 years, variant prevalence exceeded the 2.5% threshold commonly used to recommend germline testing for hereditary cancer susceptibility syndromes.
Several previously established gene-cancer associations were confirmed, including links between CDKN2A and cutaneous melanoma, pancreatic cancer, brain cancer, and head and neck cancers. Associations were also replicated for MITF E318K with melanoma and kidney cancer, and for POT1 with melanoma, thyroid cancer, and haematologic malignancies.
Novel Cancer Links Identified in Melanoma Genes
Importantly, the analysis also identified several potentially novel or inconsistently reported associations. These included links between BAP1 and prostate cancer; CDKN2A and biliary tract, breast, nonmelanoma skin, and small intestine cancers; MITF E318K and cervical, nonmelanoma skin, and nasal cavity cancers; and POT1 with myeloma.
The researchers additionally observed that individuals carrying CDKN2A pathogenic variants or MITF E318K developed cutaneous melanoma at younger ages than non-carriers.
The authors noted that most previous prevalence estimates for familial melanoma genes were derived from clinically referred families, potentially introducing ascertainment bias. By using a genome-first approach in large population cohorts, the present study offers a broader estimate of inherited melanoma susceptibility in the general population.
The findings may help refine germline testing recommendations and improve cancer risk counselling for individuals carrying familial melanoma-associated variants.
Reference
Goldstein AM et al. Prevalence of Familial Melanoma Genes and Cancer Risk Among Genomically Ascertained Individuals. JAMA Dermatol. 2026; 10.1001/jamadermatol.2026.1305.
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