Inherited Genetic Variants Associated with Melanoma BRAF/NRAS Subtypes

J Invest Dermatol. 2018 Nov;138(11):2398-2404. doi: 10.1016/j.jid.2018.04.025. Epub 2018 May 9.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • GTP Phosphohydrolases / genetics*
  • Genetic Association Studies
  • Genotype*
  • Group VI Phospholipases A2 / genetics*
  • Humans
  • Interferon Regulatory Factors / genetics*
  • Male
  • Melanoma / genetics*
  • Membrane Proteins / genetics*
  • Middle Aged
  • Mutation / genetics*
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins B-raf / genetics*
  • Risk
  • Skin Neoplasms / genetics*


  • Interferon Regulatory Factors
  • Membrane Proteins
  • interferon regulatory factor-4
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf
  • Group VI Phospholipases A2
  • PLA2G6 protein, human
  • GTP Phosphohydrolases
  • NRAS protein, human