Familial Melanoma Genes May Have Broader Cancer Impact Than Previously Recognized, Study Finds

Pathogenic variants tied to familial melanoma may be more common in the general population than previously recognized and may increase risk for a broader range of cancers beyond melanoma itself, according to a study recently published in JAMA Dermatology.¹

Gaps in Understanding Familial Melanoma Variant–Associated Cancer Risks

Cutaneous melanoma (CM) is the fifth most commonly diagnosed cancer in the US, with nearly 105,000 new cases projected in 2025.² Although approximately 10% of melanoma cases occur in families with multiple affected relatives, most prior research on inherited melanoma risk has focused on families already known to have strong cancer histories.¹ Investigators noted that this traditional approach may introduce ascertainment bias because relatives often share environmental exposures and lifestyle factors in addition to genetic risks.

To address this limitation, they conducted a “genome-first” analysis of nearly 700,000 genomically ascertained individuals from the UK and the US to estimate the prevalence of inherited pathogenic variants in 8 clinically actionable familial melanoma genes and evaluate associated cancer risks. The researchers said the findings could help refine recommendations for germline genetic testing and cancer surveillance.

They used 2 large population-scale genomic databases: the UK Biobank (UKBB) and the US Geisinger MyCode (GMC) cohort. Together, the cohorts included 696,665 genomically ascertained participants, including 469,379 individuals from UKBB and 227,286 from GMC. The GMC cohort had a mean age of 57.7 years, while UKBB participants had a mean age of 70 years. However, both groups were predominantly female and of European genetic ancestry.

Cancer registry and electronic health record data spanning 1970 through 2024 were linked with germline genomic sequencing data. Investigators evaluated rare pathogenic variants in 8 well-established familial melanoma susceptibility genes: ACD, BAP1, CDKN2A, CDK4, MITF E318K, POT1, TERF2IP, and the TERT promoter. Cancer ORs were estimated using logistic regression models adjusted for sex, birth year, BMI, and smoking status. Kaplan-Meier and Cox proportional hazards analyses were also conducted to determine the time to cancer diagnosis.

Key Findings on Familial Melanoma Variant Prevalence, Age at Onset, and Cancer Associations

Overall, the combined prevalence of pathogenic variants across the familial melanoma genes ranged from 0.5% in the GMC cohort to 0.9% in UKBB. Much of this prevalence was driven by the MITF E318K variant, which was identified in approximately 0.4% of GMC participants and 0.8% of UKBB participants.

Variants in CDKN2A, POT1, and BAP1 were considerably less common, with prevalences ranging from about 1 in 1500 to 1 in 10,000 individuals. Additionally, pathogenic variants in ACD, CDK4, and TERF2IP were extremely rare, and no pathogenic TERT promoter variants were detected in the UKBB cohort.

The prevalence of pathogenic variants exceeded the 2.5% clinical threshold commonly used to recommend genetic testing among patients considered at high risk for melanoma. Among participants with multiple CMs, pathogenic variant prevalence ranged from 5.3% in UKBB to 7.0% in GMC. Similarly, among individuals diagnosed with a first melanoma before age 40, prevalence ranged from 3.2% to 3.7%.

Time-to-event analyses further showed that carriers of CDKN2A and MITF E318K variants developed CM at significantly younger ages than noncarriers in both cohorts. Incidence curves began diverging during the fourth decade of life, supporting dermatologic surveillance beginning around age 30 for individuals with these variants.

In addition, the study replicated several previously reported associations between familial melanoma genes and internal cancers. Case-control analyses confirmed previously established cancer associations for CDKN2A (brain, head and neck, and pancreatic cancers), MITF E318K (kidney cancer), and POT1 (hematologic malignancies and thyroid cancer).

Researchers also identified potentially novel or inconsistently reported associations, including BAP1 with prostate cancer; CDKN2A with biliary tract, breast, nonmelanoma skin, and small intestine cancers; MITF E318K with cervical, nasal cavity and middle ear, and nonmelanoma skin cancers; and POT1 with myeloma.

“These findings support consideration of genetic testing in these patient groups, regardless of family history of CM or other cancers,” the authors wrote.

Implications for Genetic Testing, Future Research in Familial Melanoma

The authors acknowledged several limitations, including that some associations were based on small case counts. Also, both cohorts consisted predominantly of individuals of European ancestry, which may limit generalizability.

Still, the researchers emphasized that the study expands understanding of inherited melanoma susceptibility and associated cancer risks.

“These findings may help inform genetic testing recommendations and suggest that several familial melanoma genes may increase risk for a broader spectrum of cancers than previously recognized,” the authors concluded.

References

1. Goldstein AM, Kim J, Haley JS, et al. Prevalence of familial melanoma genes and cancer risk among genomically ascertained individuals. JAMA Dermatol. Published online May 27, 2026. doi:10.1001/jamadermatol.2026.1305
2. Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA Cancer J Clin. 2025;75(1):10-45. doi:10.3322/caac.21871