Association of inherited genetic variants with multiple primary melanoma.

Background: Recent genome-wide association studies (GWAS) have identified new susceptibility loci for melanoma, but their associations with multiple primary melanoma (MPM) are unclear.

Methods: We investigated the associations of 69 single nucleotide polymorphisms (SNPs) in 39 GWAS-identified loci with odds of MPM relative to single primary melanoma (SPM) in the international, population-based Genes, Environment, and Melanoma (GEM) study. Per-minor allele odds ratios (ORs) and 95% confidence intervals (CIs) for individuals with MPM 'cases' (n=1,205) relative to SPM 'controls' (n=2,458) were estimated using multivariable logistic regression, and polygenic risk scores (PRS) were calculated and weighted based on a 2020 GWAS meta-analysis (57 of the 68 independent GWAS SNPs available).

Results: Thirteen SNPs in 11 gene regions (PARP1, CYP1B1/RMDN3, TERT, RAPGEF5, TYRP1, MTAP, CDKN2A/CDKN2B, KLF4, TYR, SOX6, ASIP) were statistically significantly associated (P<0.05) with MPM adjusting for age, sex, age-by-sex interaction, and study center. The highest vs. lowest PRS quintile was associated with a 2.81-fold higher odds of MPM (95% CI: 2.10-3.78; P=7.5x10-13); this association was attenuated but remained statistically significant after excluding SNPs individually associated with MPM (OR=1.75, 95% CI: 1.32-2.31).

Conclusions: Inherited genetic variants spanning 11 gene regions were independently associated with MPM. Non-significant SNPs were associated with MPM when aggregated into a PRS, indicating their cumulative effect may influence MPM risk despite lacking individual statistical significance in our study population.

Impact: Our findings provide additional evidence that these loci are associated with melanoma risk and estimate the magnitude of their genetic effect on subsequent (multiple) primary melanoma risk.