title: A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families.
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.
authors.affiliation: 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), Madrid 28029, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Calvete
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Martinez
authors.affiliation: Department of Cardiology. Hospital Universitario Puerta de Hierro, Mahadahonda, Madrid 28222, Spain.|Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Garcia-Pavia
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Benitez-Buelga
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Paumard-Hernández
authors.affiliation: Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Fernandez
authors.affiliation: Department of Cardiology. Hospital Universitario Puerta de Hierro, Mahadahonda, Madrid 28222, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Dominguez
authors.affiliation: Department of Pathology. Hospital Universitario Puerta de Hierro Majadahonda, Madrid 28222, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Salas
authors.affiliation: Oncology Department, Clara Campal Comprehensive Cancer Center, Sanchinarro, Madrid 28050, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Romero-Laorden
authors.affiliation: Oncology Department, Clara Campal Comprehensive Cancer Center, Sanchinarro, Madrid 28050, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Garcia-Donas
authors.affiliation: Department of Experimental Models of Human Disease. Instituto Investigaciones Biomédicas (CSIC/UAM), Madrid 28029, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Carrillo
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid 28029, Spain.|Department of Experimental Models of Human Disease. Instituto Investigaciones Biomédicas (CSIC/UAM), Madrid 28029, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Perona
authors.affiliation: Bioinformatic Unit, Sistemas Genómicos, Paterna 46980, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Triviño
authors.affiliation: Medical Oncology Service, Hospital Universitario Lozano Blesa, Zaragoza 50009, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Andrés
authors.affiliation: Medical Oncology Service, Hospital General de Ciudad Real, Ciudad Real 13005, Spain.
authors.forename: Juana María
authors.initials: JM
authors.lastname: Cano
authors.affiliation: Familial Cancer Clinical Unit, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Bárbara
authors.initials: B
authors.lastname: Rivera
authors.affiliation: Department of Cardiology. Hospital Universitario Puerta de Hierro, Mahadahonda, Madrid 28222, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Alonso-Pulpon
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona 08908, Spain.
authors.forename: Fernando
authors.initials: F
authors.lastname: Setien
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona 08908, Spain.|Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona 08007, Spain.|Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Cytogenetics Unit, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rodriguez-Perales
authors.affiliation: Genetics Department, Rouen University Hospital, Rouen 76000, France.
authors.forename: Gaelle
authors.initials: G
authors.lastname: Bougeard
authors.affiliation: Genetics Department, Rouen University Hospital, Rouen 76000, France.
authors.forename: Tierry
authors.initials: T
authors.lastname: Frebourg
authors.affiliation: Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid 28029, Spain.|Familial Cancer Clinical Unit, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Urioste
authors.affiliation: Telomeres and Telomerase Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Blasco
authors.affiliation: 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), Madrid 28029, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
mesh_terms: D000328:Adult; D000368:Aged; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics*; D047369:Chromatin Immunoprecipitation; D003198:Computer Simulation; D005260:Female; D006338:Heart Neoplasms / Q000235:genetics*; D006394:Hemangiosarcoma / Q000235:genetics*; D057166:High-Throughput Screening Assays; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D066298:In Vitro Techniques; D016864:Li-Fraumeni Syndrome / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000089804:Shelterin Complex; D016615:Telomere / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: C440849:POT1 protein, human; D000089804:Shelterin Complex; C495901:TP53 protein, human; D034501:Telomere-Binding Proteins; D016159:Tumor Suppressor Protein p53