Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma

Nat Genet. 2014 May;46(5):482-6. doi: 10.1038/ng.2941. Epub 2014 Mar 30.

Abstract

Although CDKN2A is the most frequent high-risk melanoma susceptibility gene, the underlying genetic factors for most melanoma-prone families remain unknown. Using whole-exome sequencing, we identified a rare variant that arose as a founder mutation in the telomere shelterin gene POT1 (chromosome 7, g.124493086C>T; p.Ser270Asn) in five unrelated melanoma-prone families from Romagna, Italy. Carriers of this variant had increased telomere lengths and numbers of fragile telomeres, suggesting that this variant perturbs telomere maintenance. Two additional rare POT1 variants were identified in all cases sequenced in two separate Italian families, one variant per family, yielding a frequency for POT1 variants comparable to that for CDKN2A mutations in this population. These variants were not found in public databases or in 2,038 genotyped Italian controls. We also identified two rare recurrent POT1 variants in US and French familial melanoma cases. Our findings suggest that POT1 is a major susceptibility gene for familial melanoma in several populations.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Computational Biology
  • Exome / genetics
  • France
  • Genetic Predisposition to Disease / genetics*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Italy
  • Melanoma / genetics*
  • Models, Molecular*
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Neoplasms, Connective Tissue / genetics*
  • Pedigree
  • Sequence Alignment
  • Sequence Analysis, DNA
  • Skin Neoplasms
  • Telomere Homeostasis / genetics*
  • Telomere-Binding Proteins / chemistry
  • Telomere-Binding Proteins / genetics*
  • United States

Substances

  • POT1 protein, human
  • Telomere-Binding Proteins

Supplementary concepts

  • Melanoma, Cutaneous Malignant