A mutation in the POT1 gene is responsible for cardiac angiosarcoma in TP53-negative Li-Fraumeni-like families
Author
Calvete, Oriol; Martinez, Paula; García Pavía, Pablo
Entity
UAM. Departamento de MedicinaPublisher
Nature Publishing GroupDate
2015-09-25Citation
10.1038/ncomms9383
Nature Communications 6 (2015): Article 8383
ISSN
2041-1723DOI
10.1038/ncomms9383Funded by
We are grateful to T. de Lange (The Rockefeller University) and K. Collins (The University of California) for providing POT1 and TPP1 plasmids, respectively. J.B.’s laboratory is partially funded by the Spanish Ministry of Health PI12/00070, the Spanish Ministry of Science and Innovation (INNPRONTA 2012) and the Spanish Research Network on Rare diseases (CIBERER). O.C. is granted by the CIBERER and C.B.-B. by the PI12/00070 supported by FEDER funds. P.G.-P. is partially supported by the Spanish Ministry of Health PI11/0699, PI12/01941 and RD12/0042/0066. M.A.B.’s laboratory is funded with the Spanish Ministry of Science and Innovation, projects SAF2008-05384 and 2007-A-200950 (TELOMARKER), European Research Council Advanced grant GA#232854, the Körber Foundation, Fundación Botín and Fundación Lilly. R.P.’ lab is partially funded by PI11/0949 Supported by FEDER fundsProject
Gobierno de España. PI12/00070; Gobierno de España. PI11/0699; Gobierno de España. PI12/01941; Gobierno de España. SAF2008-05384; Gobierno de España. 2007-A-200950 TELOMARKER; info:eu-repo/grantAgreement/EC/FP7/232854Editor's Version
http://dx.doi.org/10.1038/ncomms9383Subjects
Cardiac angiosarcoma; Mutation in a breast; Telomeres; MedicinaRights
© 2015 Macmillan Publishers LimitedAbstract
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
Files in this item
Google Scholar:Calvete, Oriol
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Martinez, Paula
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García Pavía, Pablo
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Benitez-Buelga, Carlos
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Paumard Hernández, Beatriz
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Fernandez, Victoria
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Dominguez, Fernando
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Salas, Clara
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Romero-Laorden, Nuria
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Garcia-Donas, Jesus
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Carrillo, Jaime
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Perona, Rosario
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Trivinõ, Juan Carlos
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Andrés, Raquel
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Cano, Juana Mariá
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Rivera, Bárbara
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Alonso-Pulpón, Luis A.
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Setien, Fernando
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Esteller, Manel
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Rodriguez-Perales, Sandra
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Bougeard, Gaelle
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Frebourg, Tierry
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Urioste, Miguel
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Blasco, Maria A.
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Benítez, Javier
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