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

Author

Listed:
  • Oriol Calvete

    (Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain
    Center for Biomedical Network Research on Rare Diseases (CIBERER))

  • Paula Martinez

    (Telomeres and Telomerase Group, Spanish National Cancer Research Center (CNIO))

  • Pablo Garcia-Pavia

    (Mahadahonda
    Centro Nacional de Investigaciones Cardiovasculares (CNIC))

  • Carlos Benitez-Buelga

    (Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain)

  • Beatriz Paumard-Hernández

    (Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain)

  • Victoria Fernandez

    (Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain)

  • Fernando Dominguez

    (Mahadahonda)

  • Clara Salas

    (Department of Pathology. Hospital Universitario Puerta de Hierro Majadahonda)

  • Nuria Romero-Laorden

    (Clara Campal Comprehensive Cancer Center, Sanchinarro)

  • Jesus Garcia-Donas

    (Clara Campal Comprehensive Cancer Center, Sanchinarro)

  • Jaime Carrillo

    (Department of Experimental Models of Human Disease. Instituto Investigaciones Biomédicas (CSIC/UAM))

  • Rosario Perona

    (Center for Biomedical Network Research on Rare Diseases (CIBERER)
    Department of Experimental Models of Human Disease. Instituto Investigaciones Biomédicas (CSIC/UAM))

  • Juan Carlos Triviño

    (Bioinformatic Unit, Sistemas Genómicos)

  • Raquel Andrés

    (Medical Oncology Service, Hospital Universitario Lozano Blesa)

  • Juana María Cano

    (Medical Oncology Service, Hospital General de Ciudad Real)

  • Bárbara Rivera

    (Familial Cancer Clinical Unit, Spanish National Cancer Research Center (CNIO)
    Present address: Department of Human Genetics, McGill University, Montreal, Québec, Canada QC H3A 0G4.)

  • Luis Alonso-Pulpon

    (Mahadahonda)

  • Fernando Setien

    (Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL))

  • Manel Esteller

    (Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL)
    School of Medicine, University of Barcelona
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Sandra Rodriguez-Perales

    (Cytogenetics Unit, Spanish National Cancer Research Center (CNIO))

  • Gaelle Bougeard

    (Rouen University Hospital)

  • Tierry Frebourg

    (Rouen University Hospital)

  • Miguel Urioste

    (Center for Biomedical Network Research on Rare Diseases (CIBERER)
    Familial Cancer Clinical Unit, Spanish National Cancer Research Center (CNIO))

  • Maria A. Blasco

    (Telomeres and Telomerase Group, Spanish National Cancer Research Center (CNIO))

  • Javier Benítez

    (Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain
    Center for Biomedical Network Research on Rare Diseases (CIBERER))

Abstract

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.

Suggested Citation

  • Oriol Calvete & Paula Martinez & Pablo Garcia-Pavia & Carlos Benitez-Buelga & Beatriz Paumard-Hernández & Victoria Fernandez & Fernando Dominguez & Clara Salas & Nuria Romero-Laorden & Jesus Garcia-Do, 2015. "A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li–Fraumeni-like families," Nature Communications, Nature, vol. 6(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9383
    DOI: 10.1038/ncomms9383
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