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Eur J Hum Genet. 2017 Nov;25(11):1278-1281. doi: 10.1038/ejhg.2017.134. Epub 2017 Aug 30.

The wide spectrum of POT1 gene variants correlates with multiple cancer types.

Author information

1
Human Genetics Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.
2
Center for Biomedical Network Research on Rare Diseases (CIBERER), Madrid, Spain.
3
Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain.
4
Center for Biomedical Network Research on Cardiovascular Diseases (CIBERCV), Madrid, Spain.
5
Francisco de Vitoria University, Madrid, Spain.
6
Spanish National Cardiovascular Research Center (CNIC), Madrid, Spain.
7
Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Department of Genetics, Normandy Centre for Genomic and Personalized Medicine, Rouen, France.
8
Department of Pathology, Justus-Liebig-University Giessen, Giessen, Germany.
9
Hereditary Cancer Program-Medical Oncology Service, Catalan Institute of Oncology, ICO-IDIBELL and CIBERONC, Barcelona, Spain.
10
Genetic Service, Hospital Sant Pau, Barcelona, Spain.
11
Medical Oncology Service, Hospital Sant Pau, Barcelona, Spain.
12
Genetic Counseling Unit, Corporació Sanitària Parc Taulí, Barcelona, Spain.
13
Hereditary Cancer Program, Catalan Institute of Oncology, ICO-IDIBELL and CIBERONC, Barcelona, Spain.
14
Familial Cancer Clinical Unit, Spanish National Cancer Research Center (CNIO), Madrid, Spain.

Abstract

The POT1 protein binds and protects telomeres. Germline variants in the POT1 gene have recently been shown to be associated with risk of developing tumors in different tissues such as familial chronic lymphocytic leukemia, colorectal, glioma and melanoma tumors. Recently, we uncovered a variant in the POT1 gene (p.R117C) as causative of familial cardiac angiosarcomas (CAS) in Li-Fraumeni-like (LFL) syndrome families. Our in silico studies predicted that this protein had lost the ability to interact with TPP1 and single-stranded DNA. In vitro studies corroborated this prediction and showed that this lack of function leads to abnormally long telomeres. To better understand the POT1 gene and its role with tumorigenesis, we extended the study to LFL (with and without members affected with angiosarcomas (AS)) and sporadic AS and cardiac sarcomas. We found POT1 variants in the 20% of the families with members affected with AS and 10% of sporadic AS and sarcomas. In silico studies predicted that these new variants were damaging in the same manner as previously described for the POT1 p.R117C variants. The wide spectrum of variants in the POT1 gene leading to tumorigenesis in different tissues demonstrates its general importance. Study of the POT1 gene should be considered as routine diagnostic in these cancers.

PMID:
28853721
PMCID:
PMC5643968
[Available on 2018-11-01]
DOI:
10.1038/ejhg.2017.134
[Indexed for MEDLINE]

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