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

Calvete, O. ; Martinez, P. ; Garcia-Pavia, P. ; Benitez-Buelga, C. ; Paumard-Hernández, B. ; Fernandez, V. ; Dominguez, F. ; Salas, C. ; Romero-Laorden, N. ; Garcia-Donas, J. ; Carrillo, J. ; Perona, R. ; Trivinõ, J.C. ; Andrés, R. (Universidad de Zaragoza) ; Cano, J.M. ; Rivera, B. ; Alonso-Pulpon, L. ; Setien, F. ; Esteller, M. ; Rodriguez-Perales, S. ; Bougeard, G. ; Frebourg, T. ; Urioste, M. ; Blasco, M.A. ; Benítez, J.

Resumen: 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.

Idioma: Inglés

DOI: 10.1038/ncomms9383

Año: 2015

Publicado en: Nature Communications 6 (2015), 8383 [12 pp.]
ISSN: 2041-1723

Factor impacto JCR: 11.329 (2015)

Categ. JCR: MULTIDISCIPLINARY SCIENCES rank: 3 / 62 = 0.048 (2015) - Q1 - T1

Factor impacto SCIMAGO: 6.287 - Biochemistry, Genetics and Molecular Biology (miscellaneous) (Q1) - Physics and Astronomy (miscellaneous) (Q1) - Chemistry (miscellaneous) (Q1)

Financiación: info:eu-repo/grantAgreement/EC/FP7/200950/EU/Identification and characterization of novel human telomere-related biomarkers that aid cancer management by improving patient diagnosis, treatment selection, response monitoring, and drug development/TELOMARKER
Financiación: info:eu-repo/grantAgreement/EC/FP7/232854/EU/FROM TELOMERE CHROMATIN TO STEM CELL BIOLOGY/TEL STEM CEL
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI11-0699
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI11-0949
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI12-00070
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/PI12-01941
Financiación: info:eu-repo/grantAgreement/ES/ISCIII/RD12-0042-0066
Financiación: info:eu-repo/grantAgreement/ES/MICINN/SAF2008-05384

Tipo y forma: Article (Published version)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)