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Inherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes.

  • Author(s): 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
  • GEM Study Group
  • et al.
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.

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