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.
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Acknowledgements
GB’s lab is supported by the INCa, the French National Cancer Institute and the ARC Foundation for Cancer Research. CL’s lab is funded by the Asociación Española Contra el Cáncer, Spanish Health Research Foundation, Carlos III Health Institute (PIE13/00022 and PI16/00563), Catalan Health Institute and Autonomous Government of Catalonia. AB’s lab is funded by Deutsche Forschungsgemeinschaft (BR1238/8-2). JB’s lab is partially funded by CIBERER, H2020 BRIDGES project and by the Spanish Ministry of Health supported by FEDER funds (PI16/00440).
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Calvete, O., Garcia-Pavia, P., Domínguez, F. et al. The wide spectrum of POT1 gene variants correlates with multiple cancer types. Eur J Hum Genet 25, 1278–1281 (2017). https://doi.org/10.1038/ejhg.2017.134
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DOI: https://doi.org/10.1038/ejhg.2017.134
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