Genetic architecture of multiple primary cutaneous melanoma in the absence of high-penetrance susceptibility genes

Inherited genetic susceptibility to cutaneous melanoma ranges from common low-risk variants to rare high-penetrance variants. Although highly penetrant variants in genes such as CDKN2A explain many cases with multiple primary melanomas, a substantial proportion of patients are negative for known high-penetrance drivers. We studied 79 patients with 5 or more melanomas who tested negative for pathogenic variants in established high-penetrance melanoma genes, using whole-exome sequencing to identify rare coding variants and combining this with SNP array data to calculate polygenic risk scores for each individual. Although variants of uncertain or moderate effect were identified in genes involved in pigmentation and DNA damage response, no single variant explained the multiple primary melanoma phenotype in most cases. In contrast, MC1R risk alleles were significantly enriched, and polygenic risk score was markedly higher in this cohort than in population-based melanoma cases. Individuals carrying rare potentially pathogenic variants in cancer genes tended to have lower polygenic risk scores, suggesting complementary genetic architectures. These findings indicate that, in the absence of high-penetrance variants, the risk for multiple primary melanoma is largely driven by the cumulative burden of low- and moderate-risk alleles, supporting the integration of polygenic risk scores and rare variant data for melanoma risk stratification.