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In vitro phosphorylation of BRCA2 by the checkpoint kinase CHEK2.

ABSTRACT: Germline mutations in both BRCA2 and CHEK2 are associated with an increased risk for male breast cancer. To search for potential interactions between the products of these breast cancer susceptibility genes, we undertook systematic mapping of BRCA2 for potential phosphorylation sites by CHEK2. In vitro kinase assays and mass spectrometric analysis identified a 50 amino-acid fragment within the N-terminus of BRCA2 potentially targeted by CHEK2, containing two major phosphopeptides. Inducible overexpression of this peptide, but not a derivative with mutated phosphorylation sites, leads to increased chromosome fragmentation and suppression of cellular proliferation. These results suggest a link between CHEK2 and BRCA2 pathways, which may contribute to the spectrum of cancers associated with germline CHEK2 mutations.

SUBMITTER: Kim S

PROVIDER: S-EPMC2570522 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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In vitro phosphorylation of BRCA2 by the checkpoint kinase CHEK2.

Kim S S Mohapatra G G Haber D A DA

British journal of cancer 20080916 8

Germline mutations in both BRCA2 and CHEK2 are associated with an increased risk for male breast cancer. To search for potential interactions between the products of these breast cancer susceptibility genes, we undertook systematic mapping of BRCA2 for potential phosphorylation sites by CHEK2. In vitro kinase assays and mass spectrometric analysis identified a 50 amino-acid fragment within the N-terminus of BRCA2 potentially targeted by CHEK2, containing two major phosphopeptides. Inducible over ...[more]

PMID: 18797466

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Project description:ImportanceApproximately 50% of the risk for the development of testicular germ cell tumors (TGCTs) is estimated to be heritable, but no mendelian TGCT predisposition genes have yet been identified. It is hypothesized that inherited pathogenic DNA repair gene (DRG) alterations may drive susceptibility to TGCTs.ObjectiveTo systematically evaluate the enrichment of germline pathogenic variants in the mendelian cancer predisposition DRGs in patients with TGCTs vs healthy controls.Design, setting, and participantsA case-control enrichment analysis was performed from January 2016 to May 2018 to screen for 48 DRGs in 205 unselected men with TGCT and 27 173 ancestry-matched cancer-free individuals from the Exome Aggregation Consortium cohort in the discovery stage. Significant findings were selectively replicated in independent cohorts of 448 unselected men with TGCTs and 442 population-matched controls, as well as 231 high-risk men with TGCTs and 3090 ancestry-matched controls. Statistical analysis took place from January to May 2018.Main outcomes and measuresGene-level enrichment analysis of germline pathogenic variants in individuals with TGCTs relative to cancer-free controls.ResultsAmong 205 unselected men with TGCTs (mean [SD] age, 33.04 [9.67] years), 22 pathogenic germline DRG variants, one-third of which were in CHEK2 (OMIM 604373), were identified in 20 men (9.8%; 95% CI, 6.1%-14.7%). Unselected men with TGCTs were approximately 4 times more likely to carry germline loss-of-function CHEK2 variants compared with cancer-free individuals from the Exome Aggregation Consortium cohort (odds ratio [OR], 3.87; 95% CI, 1.65-8.86; nominal P = .006; q = 0.018). Similar enrichment was also seen in an independent cohort of 448 unselected Croatian men with TGCTs (mean [SD] age, 31.98 [8.11] years) vs 442 unselected Croatian men without TGCTs (at least 50 years of age at time of sample collection) (OR, >1.4; P = .03) and 231 high-risk men with TGCTs (mean [SD] age, 31.54 [9.24] years) vs 3090 men (all older than 50 years) from the Penn Medicine Biobank (OR, 6.30; 95% CI, 2.34-17.31; P = .001). The low-penetrance CHEK2 variant (p.Ile157Thr) was found to be a Croatian founder TGCT risk variant (OR, 3.93; 95% CI, 1.53-9.95; P = .002). Individuals with the pathogenic CHEK2 loss-of-function variants developed TGCTs 6 years earlier than individuals with CHEK2 wild-type alleles (5.95 years; 95% CI, 1.48-10.42; P = .009).Conclusions and relevanceThis multicenter case-control analysis of men with or without TGCTs provides evidence for CHEK2 as a novel moderate-penetrance TGCT susceptibility gene, with potential clinical utility. In addition to highlighting DNA-repair deficiency as a potential mechanism driving TGCT susceptibility, this analysis also provides new avenues to explore management strategies and biological investigations for high-risk individuals.

Dataset Information

In vitro phosphorylation of BRCA2 by the checkpoint kinase CHEK2.

Publications

In vitro phosphorylation of BRCA2 by the checkpoint kinase CHEK2.

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