A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families

Nat Commun. 2015 Sep 25:6:8383. doi: 10.1038/ncomms9383.


Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown. Here we show, by whole-exome sequencing of a TP53-negative Li-Fraumeni-like (LFL) family including CAS cases, that a missense variant (p.R117C) in POT1 (protection of telomeres 1) gene is responsible for CAS. The same gene alteration is found in two other LFL families with CAS, supporting the causal effect of the identified mutation. We extend the analysis to TP53-negative LFL families with no CAS and find the same mutation in a breast AS family. The mutation is recently found once in 121,324 studied alleles in ExAC server but it is not described in any other database or found in 1,520 Spanish controls. In silico structural analysis suggests how the mutation disrupts POT1 structure. Functional and in vitro studies demonstrate that carriers of the mutation show reduced telomere-bound POT1 levels, abnormally long telomeres and increased telomere fragility.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Blotting, Western
  • Breast Neoplasms / genetics*
  • Chromatin Immunoprecipitation
  • Computer Simulation
  • Female
  • Heart Neoplasms / genetics*
  • Hemangiosarcoma / genetics*
  • High-Throughput Screening Assays
  • Humans
  • In Situ Hybridization, Fluorescence
  • In Vitro Techniques
  • Li-Fraumeni Syndrome / genetics
  • Male
  • Middle Aged
  • Mutation, Missense
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Shelterin Complex
  • Telomere / metabolism*
  • Telomere-Binding Proteins / genetics*
  • Telomere-Binding Proteins / metabolism
  • Tumor Suppressor Protein p53 / genetics


  • POT1 protein, human
  • Shelterin Complex
  • TP53 protein, human
  • Telomere-Binding Proteins
  • Tumor Suppressor Protein p53