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

Oriol Calvete, Paula Martinez, Pablo Garcia-Pavia, Carlos Benitez-Buelga, Beatriz Paumard-Hernández, Victoria Fernandez, Fernando Dominguez, Clara Salas, Nuria Romero-Laorden, Jesus Garcia-Donas, Jaime Carrillo, Rosario Perona, Juan Carlos Triviño, Raquel Andrés, Juana María Cano, Bárbara Rivera, Luis Alonso-Pulpon, Fernando Setien, Manel Esteller, Sandra Rodriguez-Perales, Gaelle Bougeard, Tierry Frebourg, Miguel Urioste (), Maria A. Blasco () and Javier Benítez ()
Additional contact information
Oriol Calvete: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain
Paula Martinez: Telomeres and Telomerase Group, Spanish National Cancer Research Center (CNIO)
Pablo Garcia-Pavia: Mahadahonda
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)
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)
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)
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)
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

Nature Communications, 2015, vol. 6, issue 1, 1-12

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms9383

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