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Repisalud author Calvete, Oriol author Martinez, Paula author Garcia-Pavia, Pablo author Benitez-Buelga, Carlos author Paumard-Hernandez B author Fernandez, Victoria author Dominguez, Fernando author Salas, Clara author Romero-Laorden, Nuria author Garcia-Donas, Jesus author Carrillo, Jaime author Perona, Rosario author Carlos Trivino, Juan author Andrés, Raquel author Maria Cano, Juana author Rivera, Barbara author Alonso-Pulpon, Luis author Setien, Fernando author Esteller, Manel author Rodriguez Perales, Sandra author Bougeard, Gaelle author Frebourg, Tierry author Urioste, Miguel author Blasco, MA author Benitez, Javier funder Instituto de Salud Carlos III funder Ministerio de Ciencia e Innovación (España) funder Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF) funder Centro de Investigación Biomedica en Red - CIBER funder Unión Europea. Comisión Europea funder Unión Europea. Comisión Europea. European Research Council (ERC) funder Korber Foundation funder Botín Foundation funder Fundación Lilly funder ICREA 2017-11-27T13:49:50Z 2017-11-27T13:49:50Z 2015 Nat Commun. 2015; 6:8383 10.1038/ncomms9383 2041-1723 Nature Communications 26403419 http://hdl.handle.net/20.500.12105/5394 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. eng TELOMERE LENGTH QUANTITATIVE PCR PROTEIN VARIANTS REQUIREMENTS MAINTENANCE PREDISPOSE EXPRESSION PREDICTION PROTECTION A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families journal article URL https://repisalud.isciii.es/bitstreams/faaefcb8-3795-4439-801f-23a1b9e5a20e/download File MD5 ed173d2c0027f823e7a8c192a5cc3f00 1950122 application/pdf AmutationinthePOT1_2015.pdf URL https://repisalud.isciii.es/bitstreams/6e169fa8-3a0a-4100-87a9-0e9a8b182066/download File MD5 d4cc9042e27f13c2e4f1ddb4ff72e30f 277028 application/pdf AmutationinthePOT1_2015_suppl.pdf URL https://repisalud.isciii.es/bitstreams/b14ab4da-3d18-452d-b1db-fb2c9f1a1451/download File MD5 18a1c5d075f57d43997ccc3f74fb4e96 74280 text/plain AmutationinthePOT1_2015.pdf.txt URL https://repisalud.isciii.es/bitstreams/bb010b45-fb50-4794-baa2-e12100f4acbe/download File MD5 f2ee3c50bfd0f7dcbd88a65da829544d 7895 text/plain AmutationinthePOT1_2015_suppl.pdf.txt