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Functionally Null <i>RAD51D</i> Missense Mutation Associates Strongly with Ovarian Carcinoma.

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Date
2017-08
ICR Author
Lord, Christopher
Author
Rivera, B
Di Iorio, M
Frankum, J
Nadaf, J
Fahiminiya, S
Arcand, SL
Burk, DL
Grapton, D
Tomiak, E
Hastings, V
Hamel, N
Wagener, R
Aleynikova, O
Giroux, S
Hamdan, FF
Dionne-Laporte, A
Zogopoulos, G
Rousseau, F
Berghuis, AM
Provencher, D
Rouleau, GA
Michaud, JL
Mes-Masson, A-M
Majewski, J
Bens, S
Siebert, R
Narod, SA
Akbari, MR
Lord, CJ
Tonin, PN
Orthwein, A
Foulkes, WD
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Type
Journal Article
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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 .
URI
https://repository.icr.ac.uk/handle/internal/4080
DOI
https://doi.org/10.1158/0008-5472.can-17-0190
Collections
  • Breast Cancer Research
  • Molecular Pathology
Subject
Humans
Ovarian Neoplasms
DNA-Binding Proteins
Case-Control Studies
Pedigree
Genotype
Mutation
Mutation, Missense
Polymorphism, Single Nucleotide
Adult
Aged
Middle Aged
Female
Research team
Gene Function
Language
eng
Date accepted
2017-06-06
License start date
2017-08
Citation
Cancer research, 2017, 77 (16), pp. 4517 - 4529

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