Association of Inherited Genetic Variants with Multiple Primary Melanoma

Abstract

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 SNPs in 39 GWAS-identified loci with odds of MPM relative to single primary melanoma in the international, population-based Genes, Environment, and Melanoma study. Per-minor-allele ORs and 95% confidence intervals (CI) for individuals with MPM "cases" (n = 1,205) relative to single primary melanoma "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, and ASIP) were statistically significantly associated (P < 0.05) with MPM adjusting for age, sex, age-by-sex interaction, and study center. The highest versus lowest PRS quintile was associated with a 2.81-fold higher odds of MPM (95% CI, 2.10-3.78; P = 7.5 × 10-13); 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. Nonsignificant SNPs were associated with MPM when aggregated into a PRS, indicating that 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.

Figure 1.

Loci with single nucleotide polymorphisms (SNPs) associated with multiple primary melanoma relative to single primary melanoma in the Genes, Environment, and Melanoma (GEM) study, color coded according to chromosome location. Gene regions with statistically significant SNPs (P < 0.05, as indicated by the dotted line) are labeled. Note that this figure shows SNPs investigated in the current study as well those previously investigated in relation to multiple primary melanoma risk in the GEM study (statistically significant variants in MX2, MITF, and MC1R reported in Gibbs et al. [Ref. 5], Berwick et al. [Ref. 18], Kanetsky et al. [Ref. 19], respectively). In total, this includes variants within 47 (87%) of the 54 melanoma susceptibility loci recently identified or confirmed in the largest melanoma meta-GWAS to date (Landi et al., Ref. 7).

Figure 2.

SNP associations with MPM vs. SPM in the Genes, Environment, and Melanoma (GEM) study compared to their associations with melanoma cases vs. controls from the largest melanoma meta-GWAS to date (Landi et al., Ref. 7). Per effect allele beta estimates and standard errors are shown as they were reported in GWAS. Of the 68 independent SNPs in 54 loci identified by Landi et al., 57 SNPs (84%) in 47 loci (87%) have been genotyped in GEM and are shown here (detailed information in Supplementary Table S2). ‘*’ denotes SNPs that were statistically significant (P<0.05) in the GEM study.