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Nat Commun. 2015 Sep 25;6:8383. doi: 10.1038/ncomms9383.

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

Author information

1
Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernandez Almagro 3, Madrid 28029, Spain.
2
Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid 28029, Spain.
3
Telomeres and Telomerase Group, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
4
Department of Cardiology. Hospital Universitario Puerta de Hierro, Mahadahonda, Madrid 28222, Spain.
5
Department of Cardiovascular Development and Repair, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid 28029, Spain.
6
Department of Pathology. Hospital Universitario Puerta de Hierro Majadahonda, Madrid 28222, Spain.
7
Oncology Department, Clara Campal Comprehensive Cancer Center, Sanchinarro, Madrid 28050, Spain.
8
Department of Experimental Models of Human Disease. Instituto Investigaciones Biomédicas (CSIC/UAM), Madrid 28029, Spain.
9
Bioinformatic Unit, Sistemas Genómicos, Paterna 46980, Spain.
10
Medical Oncology Service, Hospital Universitario Lozano Blesa, Zaragoza 50009, Spain.
11
Medical Oncology Service, Hospital General de Ciudad Real, Ciudad Real 13005, Spain.
12
Familial Cancer Clinical Unit, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
13
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona 08908, Spain.
14
Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona 08007, Spain.
15
Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain.
16
Cytogenetics Unit, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain.
17
Genetics Department, Rouen University Hospital, Rouen 76000, France.

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.

PMID:
26403419
PMCID:
PMC4598567
DOI:
10.1038/ncomms9383
[Indexed for MEDLINE]
Free PMC Article
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