Gibbs David C, Small Brittany M, Autuori Isidora, Leong Siok F, Ali Emily, Kenney Jessica, Luo Li, Kanetsky Peter A, Busam Klaus J, Cust Anne E, Anton-Culver Hoda, Gallagher Richard P, Zanetti Roberto, Rosso Stefano, Sacchetto Lidia, Edmiston Sharon N, Conway Kathleen, Ollila David W, Begg Colin B, Berwick Marianne, Orlow Irene, Thomas Nancy E
Department of Dermatology, Emory University, Atlanta, Georgia.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Cancer Epidemiol Biomarkers Prev. 2025 May 2;34(5):805-814. doi: 10.1158/1055-9965.EPI-24-1442.
Recent genome-wide association studies (GWAS) have identified new susceptibility loci for melanoma, but their associations with multiple primary melanoma (MPM) are unclear.
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).
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).
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.
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.
近期全基因组关联研究（GWAS）已确定了黑色素瘤的新易感基因座，但它们与多发性原发性黑色素瘤（MPM）的关联尚不清楚。
在国际、基于人群的基因、环境与黑色素瘤研究中，我们调查了39个GWAS确定基因座中的69个单核苷酸多态性（SNP）与MPM相对于单发性原发性黑色素瘤的比值比。使用多变量逻辑回归估计MPM“病例”（n = 1205）相对于单发性原发性黑色素瘤“对照”（n = 2458）个体的每小等位基因比值比（OR）和95%置信区间（CI），并根据2020年GWAS荟萃分析（68个独立GWAS SNP中的57个可用）计算并加权多基因风险评分（PRS）。
11个基因区域（PARP1、CYP1B1/RMDN3、TERT、RAPGEF5、TYRP1、MTAP、CDKN2A/CDKN2B、KLF4、TYR、SOX6和ASIP）中的13个SNP在调整年龄、性别、年龄与性别的交互作用以及研究中心后与MPM具有统计学显著关联（P < 0.05）。最高与最低PRS五分位数与MPM的比值比高2.81倍相关（95% CI，2.10 - 3.78；P = 7.5 × 10 - 13）；在排除与MPM单独相关的SNP后，这种关联减弱但仍具有统计学显著性（OR = 1.75，95% CI，1.32 - 2.31）。
跨越11个基因区域的遗传变异与MPM独立相关。无统计学显著性的SNP在汇总到PRS中时与MPM相关，表明它们的累积效应可能影响MPM风险，尽管在我们的研究人群中缺乏个体统计学显著性。
我们的研究结果提供了额外证据，证明这些基因座与黑色素瘤风险相关，并估计了它们对后续（多发性）原发性黑色素瘤风险的遗传效应大小。
