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

被引：134

作者：

Calvete, Oriol ^{[1
,2
]}

Martinez, Paula ^{[3
]}

Garcia-Pavia, Pablo ^{[4
,5
]}

Benitez-Buelga, Carlos ^{[1
]}

Paumard-Hernandez, Beatriz ^{[1
]}

Fernandez, Victoria ^{[1
]}

Dominguez, Fernando ^{[4
]}

Salas, Clara ^{[6
]}

Romero-Laorden, Nuria ^{[7
]}

Garcia-Donas, Jesus ^{[7
]}

Carrillo, Jaime ^{[8
]}

Perona, Rosario ^{[2
,8
]}

Carlos Trivino, Juan ^{[9
]}

Andres, Raquel ^{[10
]}

Maria Cano, Juana ^{[11
]}

Rivera, Barbara ^{[12
]}

Alonso-Pulpon, Luis ^{[4
]}

Setien, Fernando ^{[13
]}

Esteller, Manel ^{[13
,14
,15
]}

Rodriguez-Perales, Sandra ^{[16
]}

Bougeard, Gaelle ^{[17
]}

Frebourg, Tierry ^{[17
]}

Urioste, Miguel ^{[2
,12
]}

Blasco, Maria A. ^{[3
]}

Benitez, Javier ^{[1
,2
]}

机构：

[1] Spanish Natl Canc Res Ctr CNIO, Human Genet Grp, Madrid 28029, Spain

[2] Ctr Biomed Network Res Rare Dis CIBERER, Madrid 28029, Spain

[3] Spanish Natl Canc Res Ctr CNIO, Telomeres & Telomerase Grp, Madrid 28029, Spain

[4] Hosp Univ Puerta Hierro, Dept Cardiol, Madrid 28222, Spain

[5] Ctr Nacl Invest Cardiovasc CNIC, Dept Cardiovasc Dev & Repair, Madrid 28029, Spain

[6] Hosp Univ Puerta Hierro Majadahonda, Dept Pathol, Madrid 28222, Spain

[7] Clara Campal Comprehens Canc Ctr, Dept Oncol, Madrid 28050, Spain

[8] UAM, CSIC, Inst Invest Biomed, Dept Expt Models Human Dis, Madrid 28029, Spain

[9] Sistemas Genom, Bioinformat Unit, Paterna 46980, Spain

[10] Hosp Univ Lozano Blesa, Med Oncol Serv, Zaragoza 50009, Spain

[11] Hosp Gen Ciudad Real, Med Oncol Serv, Ciudad Real 13005, Spain

[12] Spanish Natl Canc Res Ctr CNIO, Familial Canc Clin Unit, Madrid 28029, Spain

[13] Bellvitge Biomed Res Inst IDIBELL, Canc Epigenet & Biol Program PEBC, Barcelona 08908, Spain

[14] Univ Barcelona, Sch Med, Dept Physiol Sci 2, E-08007 Barcelona, Spain

[15] ICREA, Barcelona 08010, Spain

[16] Spanish Natl Canc Res Ctr CNIO, Cytogenet Unit, Madrid 28029, Spain

[17] Rouen Univ Hosp, Dept Genet, F-76000 Rouen, France

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

欧洲研究理事会;

关键词：

TELOMERE LENGTH; QUANTITATIVE PCR; PROTEIN; VARIANTS; REQUIREMENTS; PREDISPOSE; EXPRESSION; PREDICTION; FUSIONS; COMPLEX;

D O I：

10.1038/ncomms9383

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

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.

引用

页数：12

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