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Clin Cancer Res. 2018 Jan 15;24(2):326-333. doi: 10.1158/1078-0432.CCR-17-2136. Epub 2017 Oct 30.

Location of Mutation in BRCA2 Gene and Survival in Patients with Ovarian Cancer.

Author information

1
Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland. intidhar.labidi-galy@hcuge.ch.
2
Department of Oncology, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
3
Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France.
4
Inserm U830, PSL Research University, Institut Curie, Paris, France.
5
Department of Surgery, Centre Léon Bérard, Lyon, France.
6
Institut du Cancer Jean Mermoz, Lyon, France.
7
Department of Gynecology, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
8
Department of Medical Oncology, Centre Léon Bérard, Lyon, France.
9
Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
10
Department of Genetic, Laboratory and Pathology Medicine, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
11
Division of Genetics, Pôle de Médecine diagnostique et théranostique, Institut Curie, Paris, France.
12
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
13
Division of Molecular Genetics, Hospices Civiles de Lyon, Lyon, France.
14
Unit of Prevention and Genetic Epidemiology, UMR CNRS 5558, Centre Léon Bérard, Lyon, France.
15
University Claude Bernard (UCBL Lyon1), Lyon France.

Abstract

Purpose: BRCA2 plays a central role in homologous recombination by loading RAD51 on DNA breaks. The objective of this study is to determine whether the location of mutations in the RAD51-binding domain (RAD51-BD; exon 11) of BRCA2 gene affects the clinical outcome of ovarian cancer patients.Experimental Design: A study cohort of 353 women with ovarian cancer who underwent genetic germline testing for BRCA1 and BRCA2 genes was identified. Progression-free survival (PFS), platinum-free interval (PFI), and overall survival (OS) were analyzed. The Cancer Genome Atlas (TCGA) cohort of ovarian cancer (n = 316) was used as a validation cohort.Results: In the study cohort, 78 patients were carriers of germline mutations of BRCA2 After adjustment for FIGO stage and macroscopic residual disease, BRCA2 carriers with truncating mutations in the RAD51-BD have significantly prolonged 5-year PFS [58%; adjusted HR, 0.36; 95% confidence interval (CI), 0.20-0.64; P = 0.001] and prolonged PFI (29.7 vs. 15.5 months, P = 0.011), compared with noncarriers. BRCA2 carriers with mutations located in other domains of the gene do not have prolonged 5-year PFS (28%, adjusted HR, 0.67; 95% CI, 0.42-1.07; P = 0.094) or PFI (19 vs. 15.5 months, P = 0.146). In the TCGA cohort, only BRCA2 carriers harboring germline or somatic mutations in the RAD51-BD have prolonged 5-year PFS (46%; adjusted HR, 0.30; 95% CI, 0.13-0.68; P = 0.004) and 5-year OS (78%; adjusted HR, 0.09; 95% CI, 0.02-0.38; P = 0.001).Conclusions: Among ovarian cancer patients, BRCA2 carriers with mutations located in the RAD51-BD (exon 11) have prolonged PFS, PFI, and OS. Clin Cancer Res; 24(2); 326-33. ©2017 AACR.

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