1. Inherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes
- Author
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Thomas, Nancy E, Edmiston, Sharon N, Orlow, Irene, Kanetsky, Peter A, Luo, Li, Gibbs, David C, Parrish, Eloise A, Hao, Honglin, Busam, Klaus J, Armstrong, Bruce K, Kricker, Anne, Cust, Anne E, Anton-Culver, Hoda, Gruber, Stephen B, Gallagher, Richard P, Zanetti, Roberto, Rosso, Stefano, Sacchetto, Lidia, Dwyer, Terence, Ollila, David W, Begg, Colin B, Berwick, Marianne, Conway, Kathleen, Begg, Colin, Roy, Pampa, Reiner, Anne, Leong, Siok, Guerrero, Sergio Corrales, Sadeghi, Keimya, Boyce, Tawny W, Venn, Alison, Tucker, Paul, Marrett, Loraine D, From, Lynn, Huang, Shu-Chen, Groben, Pamela A, Parrish, Eloise, Frank, Jill S, Rebbeck, Timothy R, Taylor, Julia Lee, and Madronich, Sasha
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Human Genome ,Cancer ,Genetic Testing ,Genetics ,Aetiology ,2.1 Biological and endogenous factors ,Adult ,Aged ,Female ,GTP Phosphohydrolases ,Genetic Association Studies ,Genotype ,Group VI Phospholipases A2 ,Humans ,Interferon Regulatory Factors ,Male ,Melanoma ,Membrane Proteins ,Middle Aged ,Mutation ,Polymorphism ,Single Nucleotide ,Proto-Oncogene Proteins B-raf ,Risk ,Skin Neoplasms ,GEM Study Group ,Clinical Sciences ,Dermatology & Venereal Diseases ,Clinical sciences - Abstract
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 (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.
- Published
- 2018