Genetic variation at KIT locus may predispose to melanoma

Pigment Cell Melanoma Res. 2013 Jan;26(1):88-96. doi: 10.1111/pcmr.12032. Epub 2012 Nov 23.

Abstract

As loss of KIT frequently occurs in melanoma progression, we hypothesized that KIT is implicated in predisposition to melanoma (MM). Thus, we sequenced the KIT coding region in 112 familial MM cases and 143 matched controls and genotyped tag single-nucleotide polymorphisms (SNPs) in two cohorts of melanoma patients and matched controls. Five rare KIT substitutions, all predicted possibly or probably deleterious, were identified in five patients, but none in controls [RR = 2.26 (1.26-2.26)]. Expressed in melanocyte lines, three substitutions inhibited KIT signaling. Comparison with exomes database (7020 alleles) confirmed a significant excess of rare deleterious KIT substitutions in patients. Additionally, a common SNP, rs2237028, was associated with MM risk, and 6 KIT variants were associated with nevus count. Our data strongly suggest that rare KIT substitutions predispose to melanoma and that common variants at KIT locus may also impact nevus count and melanoma risk.

MeSH terms

  • Case-Control Studies
  • Exome / genetics
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Humans
  • Melanoma / genetics*
  • Phosphorylation
  • Pigmentation / genetics
  • Polymorphism, Single Nucleotide / genetics*
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-kit / chemistry
  • Proto-Oncogene Proteins c-kit / genetics*
  • Sequence Analysis, DNA
  • Skin Neoplasms / genetics*

Substances

  • Proto-Oncogene Proteins c-kit