Genetic Variants in Fanconi Anemia Pathway Genes BRCA2 and FANCA Predict Melanoma Survival

J Invest Dermatol. 2015 Feb;135(2):542-550. doi: 10.1038/jid.2014.416. Epub 2014 Sep 22.

Abstract

Cutaneous melanoma (CM) is the most lethal skin cancer. The Fanconi anemia (FA) pathway involved in DNA crosslink repair may affect CM susceptibility and prognosis. Using data derived from published genome-wide association study, we comprehensively analyzed the associations of 2,339 common single-nucleotide polymorphisms (SNPs) in 14 autosomal FA genes with overall survival (OS) in 858 CM patients. By performing false-positive report probability corrections and stepwise Cox proportional hazards regression analyses, we identified significant associations between CM OS and four putatively functional SNPs: BRCA2 rs10492396 (AG vs. GG: adjusted hazard ratio (adjHR)=1.85, 95% confidence interval (CI)=1.16-2.95, P=0.010), rs206118 (CC vs. TT+TC: adjHR=2.44, 95% CI=1.27-4.67, P=0.007), rs3752447 (CC vs. TT+TC: adjHR=2.10, 95% CI=1.38-3.18, P=0.0005), and FANCA rs62068372 (TT vs. CC+CT: adjHR=1.85, 95% CI=1.27-2.69, P=0.001). Moreover, patients with an increasing number of unfavorable genotypes (NUG) of these loci had markedly reduced OS and melanoma-specific survival (MSS). The final model incorporating with NUG, tumor stage, and Breslow thickness showed an improved discriminatory ability to classify both 5-year OS and 5-year MSS. Additional investigations, preferably prospective studies, are needed to validate our findings.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Computational Biology
  • Fanconi Anemia / genetics*
  • Fanconi Anemia Complementation Group A Protein / genetics*
  • Female
  • Genes, BRCA2*
  • Genetic Variation*
  • Humans
  • Male
  • Melanoma / genetics*
  • Melanoma / mortality
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Proportional Hazards Models
  • ROC Curve
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / mortality

Substances

  • FANCA protein, human
  • Fanconi Anemia Complementation Group A Protein