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

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 s...

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Detalhes bibliográficos
Autores: Calvete, Oriol, Martinez, Paula, Garcia-Pavia, Pablo, Benitez-Buelga, Carlos, Paumard-Hernandez B, Fernandez, Victoria, Dominguez, Fernando, Salas, Clara, Romero-Laorden, Nuria, Garcia-Donas, Jesus, Carrillo, Jaime, Perona, Rosario, Carlos Trivino, Juan, Andrés, Raquel, Maria Cano, Juana, Rivera, Barbara, Alonso-Pulpon, Luis, Setien, Fernando, Esteller, Manel, Rodriguez Perales, Sandra, Bougeard, Gaelle, Frebourg, Tierry, Urioste, Miguel, Blasco, MA, Benitez, Javier
Formato: artículo
Fecha de publicación:2015
País:España
Recursos:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/5394
Acesso em linha:http://hdl.handle.net/20.500.12105/5394
Access Level:acceso abierto
Palavra-chave:TELOMERE LENGTH
QUANTITATIVE PCR
PROTEIN
VARIANTS
REQUIREMENTS
MAINTENANCE
PREDISPOSE
EXPRESSION
PREDICTION
PROTECTION
Descrição
Resumo: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.

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