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

Oriol Calvete,Manel Esteller,Nuria Romero-Laorden,Bárbara Rivera,Juana María Cano,Miguel Urioste,Jaime Carrillo,Juan Carlos Triviño,Rosario Perona,Raquel Andrés,Clara Salas,Fernando Setién ,Fernándo Domínguez ,Paula Martínez ,Victoria Fernández ,T Frébourg ,Carlos Benítez‐Buelga ,Jesús García-Donás ,Pablo García‐Pavía ,Beatriz Paumard‐Hernández ,Luis Alonso‐Pulpón ,Gaëlle Bougeard ,Sandra Rodríguez-Perales ,Marı́a A Blasco ,Javier Benı́tez

doi:10.1038/ncomms9383

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.

Highlights

Cardiac angiosarcoma (CAS) is a rare malignant tumour whose genetic basis is unknown
POT1 is a component of the so-called shelterin complex (POT1, TRF1, TRF2, TIN2, TPP1 and RAP1) that binds to telomeres and has fundamental roles in chromosome stability and regulation of telomerase activity at chromosome ends8,9
To complete the study of these putative conformational changes observed in POT1R117C, PACC scores for the same residues were calculated for predicted protein models encompassing previously described mutations in the OB1 domain in melanoma and glioma tumours (p.Y89C and p.Q94E20, p.G95C22, and p.R137H21)

Summary

Results

Whole-exome sequencing (WES) and candidate variant studies. A TP53-negative LFL Spanish family with three CAS cases and eight members with different tumours across generations were ascertained from the Cancer Genetic Consultancy of CNIO, (Fig. 1 and Table 1). Two members affected by CAS (II-10 and III-13) were selected for WES (Fig. 1; Methods for details).

CM þ AS 1 ALL þ BA 1 CM þ BA 1 CM þ BA þ BC

37 High exposure

II-1 III-14 III-16 II-4 II-9 III-15 III-17

Methods