Association of inherited genetic variants with multiple primary melanoma Journal Article
| Authors: | Gibbs, D. C.; Small, B. M.; Autuori, I.; Leong, S. F.; Ali, E.; Kenney, J.; Luo, L.; Kanetsky, P. A.; Busam, K. J.; Cust, A. E.; Anton-Culver, H.; Gallagher, R. P.; Zanetti, R.; Rosso, S.; Sacchetto, L.; Edmiston, S. N.; Conway, K.; Ollila, D. W.; Begg, C. B.; Berwick, M.; Orlow, I.; Thomas, N. E.; on behalf of the GEM Study Group |
| Article Title: | 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. ©2025 American Association for Cancer Research. |
| Keywords: | adult; controlled study; aged; middle aged; single nucleotide polymorphism; case control study; genetics; case-control studies; polymorphism, single nucleotide; sensitivity analysis; chromosome; phenotype; allele; genetic predisposition to disease; melanoma; gene expression; skin neoplasms; gene locus; genetic variability; genotype; gene frequency; genome-wide association study; pathology; risk factor; confidence interval; skin tumor; cytochrome p450 1b1; cyclin dependent kinase inhibitor 2a; genetic predisposition; neoplasms, multiple primary; kruppel like factor 4; binomial distribution; genotyping; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase 1; cyclin dependent kinase inhibitor 2b; telomere length; multiple primary melanoma; tert gene; humans; human; male; female; article; mtap gene; krüppel-like factor 4; genetic risk score; transcription factor sox6; tyr gene; multiple primary neoplasm; klf4 protein, human; asip gene; rapgef5 gene; rmdn3 gene; tyrp1 gene |
| Journal Title: | Cancer Epidemiology Biomarkers and Prevention |
| Volume: | 34 |
| Issue: | 5 |
| ISSN: | 1055-9965 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2025-05-01 |
| Start Page: | 805 |
| End Page: | 814 |
| Language: | English |
| DOI: | 10.1158/1055-9965.Epi-24-1442 |
| PUBMED: | 40036058 |
| PROVIDER: | scopus |
| PMCID: | PMC12067251 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Nancy E. Thomas -- Source: Scopus |
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