biostudies-literatureThomas NENIEHS NIH HHSNCI NIH HHSNIGMS NIH HHS2398-2404https://www.ebi.ac.uk/biostudies/studies/S-EPMC6200630biostudies-literatureUnknown138(11)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 Study, 1,223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms identified as low-penetrant melanoma-risk variants. We used multinomial logistic regression to simultaneously examine each single-nucleotide polymorphism'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 (odds ratio [OR] = 0.59, 95% confidence interval [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 (P_global = 0.001) passed false discovery (P_global = 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 (P_global) 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.The Journal of investigative dermatologyInherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes.PMC6200630R01 CA112524R03 CA173806P30 CA008748R03 CA125829P30 ES010126P30 CA014089P01 CA206980P30 CA016086T32 GM008169U01 CA083180K07 CA102096R01 CA112243R01 CA098438Edmiston SNCust AEGEM Study GroupAnton-Culver HMarrett LDKanetsky PAConway KSacchetto LParrish EAHuang SCBegg CBDwyer TRoy PFrom LArmstrong BKZanetti RRebbeck TRMadronich SBerwick MLee Taylor JOrlow ILeong SSadeghi KReiner ABoyce TWFrank JSOllila DWGruber SBParrish EVenn ARosso SLuo LGibbs DCGuerrero SCTucker PBegg CHao HGroben PAKricker AThomas NEBusam KJGallagher RPfalseInherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes.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 Study, 1,223 European-origin participants had their incident invasive primary melanomas screened for BRAF/NRAS mutations and germline DNA genotyped for 47 single-nucleotide polymorphisms identified as low-penetrant melanoma-risk variants. We used multinomial logistic regression to simultaneously examine each single-nucleotide polymorphism'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 (odds ratio [OR] = 0.59, 95% confidence interval [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 (P_global = 0.001) passed false discovery (P_global = 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 (P_global) 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.2018-01-01T00:00:00Z2018 Nov2024-11-08T22:37:49.491Z2019-11-07T08:01:41ZS-EPMC62006302975302910.1016/j.jid.2018.04.025