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

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.

Germ line mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia

“…These findings are consistent with the evidence of linkage of familial CLL to chromosomes 7q31.32-q33 and 16q12.2-q23.1 that we previously observed (supplemental Figure 5). 43 Germ line disruptive variants within shelterin genes have recently been implicated in predisposition to familial melanoma, 39,40 cardiac angiosarcoma, 44 glioma, 45 and colorectal cancer, 46 whereas somatic mutations of POT1 are detectable in 3.5% of all CLL and 9% of encoding immunoglobulin heavy chain variable-unmutated CLL, 37 and were also identified in 10% of patients with cutaneous T-cell lymphoma.…”

“…Additionally, in our case-control analysis, the POT1 p.Gln376Arg mutation was shown to confer a modest 3.6-fold increase in risk of CLL. Furthermore, the absence of significant LOH in the tumors of carriers, when examined, 44 suggests that mutations in the shelterin complex genes do not function as high penetrance tumor suppressors but rather as moderate penetrance alleles.…”

“…Germ line disruptive mutations in POT1 have previously been associated with susceptibility to melanoma in 9 families 39,40 and glioma in 3 families. 45 Furthermore, recent studies have identified POT1 p.Arg117Cys in 4 Li-Fraumeni-like syndrome families, 44 and ACD and TERF2IP mutations in 8 melanoma families. 56 None of the mutation carriers in the melanoma families featured cases of glioma or CLL.…”

Candidate driver genes involved in genome maintenance and DNA repair in Sézary syndrome

“…13 In addition, the POT1 R117C variant has recently been identified as the cause of an inherited cancer syndrome in which loss of function causes an age-related increase in telomere length and genomic instability, contributing to the development of malignancies including lymphomas. 35 ATM is a PI3 kinase involved in the recognition of DNA double-strand breaks and recruitment of telomerase, and copy number losses have recently been reported in SS. 3,58 The ATM E2423K variant is associated with loss of function in non-small-cell lung cancer.…”

Fanconi anemia proteins in telomere maintenance

“…Recent studies have linked abnormally long telomeres to tumorigenesis [6, 8, 56–59]. Interestingly, both FANCD2 and SLX4 localize to telomeres and are required for maintaining long telomeres in ALT cells.…”