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BRAF and NRAS mutations arise early in melanoma development but their associations with low-penetrance melanoma susceptibility loci remain unknown. In the Genes, Environment and Melanoma (GEM) Study, 1223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms (SNPs) identified as low-penetrant melanoma risk variants. We used multinomial logistic regression to simultaneously examine each SNP's relationship to BRAF V600E, BRAF V600K, BRAF other, and NRAS+ relative to BRAF-/NRAS- melanoma adjusted for study features. IRF4 rs12203592*T was associated with BRAF V600E (OR = 0.59, 95% CI = 0.43-0.79) and V600K (OR = 0.65, 95% CI = 0.41-1.03), but not BRAF other or NRAS+ melanoma. A global test of etiologic heterogeneity (Pglobal = 0.001) passed false discovery (Pglobal = 0.0026). PLA2G6 rs132985*T was associated with BRAF V600E (OR = 1.32, 95% CI = 1.05-1.67) and BRAF other (OR = 1.82, 95% CI = 1.11-2.98), but not BRAF V600K or NRAS+ melanoma. The test for etiologic heterogeneity (Pglobal) was 0.005. The IRF4 rs12203592 associations were slightly attenuated after adjustment for melanoma-risk phenotypes. The PLA2G6 rs132985 associations were independent of phenotypes. IRF4 and PLA2G6 inherited genotypes may influence melanoma BRAF/NRAS subtype development.

Original publication




Journal article


J Invest Dermatol

Publication Date



IRF4, Interferon Regulatory Factor-4, Melanoma, PLA2G6, dermatology, epidemiology, freckling, genotype, hair color, melanocytes, nevus, phospholipase A2 group VI, pigmentation, polymorphism, population-based