Format

Send to

Choose Destination
Cancer Res. 2017 Aug 15;77(16):4517-4529. doi: 10.1158/0008-5472.CAN-17-0190. Epub 2017 Jun 23.

Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma.

Author information

1
Department of Human Genetics, McGill University, Montreal, Canada.
2
Lady Davis Institute, Montreal, Canada.
3
The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom.
4
Genome Quebec Innovation Centre, Montreal, Canada.
5
Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, Canada.
6
Department of Biochemistry, McGill University, Montreal, Canada.
7
Department of Genetics, University of Ottawa, Children's Hospital of Eastern Ontario, Canada.
8
Institute of Human Genetics, University of Ulm and University of Ulm Medical Center, Ulm, Germany.
9
Department of pathology, Jewish General Hospital, Montreal, Canada.
10
University of Laval and CHU Research Centre, Quebec; Canada.
11
CHU Sainte-Justine Research Center, Montreal, Canada.
12
Montreal Neurological Institute, McGill University, Montreal, Canada.
13
The Goodman Cancer Research Centre, McGill University, Montreal, Canada.
14
Centre de recherche du CHUM and Institut du cancer de Montréal, University of Montreal, Montreal, Canada.
15
Dalla Lana School of Public Health, Toronto, Canada.
16
Women's College Hospital, Toronto, Canada.
17
Department of Medicine, McGill University, Montreal, Canada.
18
Department of Oncology, McGill University, Montreal, Canada.
19
Department of Human Genetics, McGill University, Montreal, Canada. william.foulkes@mcgill.ca.
20
Department of Medical Genetics, Research Institute, McGill University Health Centre, Montreal, Canada.

Abstract

RAD51D is a key player in DNA repair by homologous recombination (HR), and RAD51D truncating variant carriers have an increased risk for ovarian cancer. However, the contribution of nontruncating RAD51D variants to cancer predisposition remains uncertain. Using deep sequencing and case-control genotyping studies, we show that in French Canadians, the missense RAD51D variant c.620C>T;p.S207L is highly prevalent and is associated with a significantly increased risk for ovarian high-grade serous carcinoma (HGSC; 3.8% cases vs. 0.2% controls). The frequency of the p.S207L variant did not significantly differ from that of controls in breast, endometrial, pancreas, or colorectal adenocarcinomas. Functionally, we show that this mutation impairs HR by disrupting the RAD51D-XRCC2 interaction and confers PARP inhibitor sensitivity. These results highlight the importance of a functional RAD51D-XRCC2 interaction to promote HR and prevent the development of HGSC. This study identifies c.620C>T;p.S207L as the first bona fide pathogenic RAD51D missense cancer susceptibility allele and supports the use of targeted PARP-inhibitor therapies in ovarian cancer patients carrying deleterious missense RAD51D variants. Cancer Res; 77(16); 4517-29. ©2017 AACR.

PMID:
28646019
DOI:
10.1158/0008-5472.CAN-17-0190
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center