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Ref Type Journal Article
PMID (28646019)
Authors 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 AM, Majewski J, Bens S, Siebert R, Narod SA, Akbari MR, Lord CJ, Tonin PN, Orthwein A, Foulkes WD
Title Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma.
Journal Cancer research
Vol 77
Issue 16
Date 2017 Aug 15
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
RAD51D D206A missense loss of function RAD51D D206A lies within the Walker B motif region of the Rad51d protein (PMID: 30836272). D206A fails to restore mitomycin sensitivity in cell culture (PMID: 16717288), and demonstrates reduced ability to bind Xrcc2 and Rad51c in yeast and in cell culture assays (PMID: 16717288, PMID: 28646019).
RAD51D E233G missense unknown RAD51D E233G lies within the ATPase domain of the Rad51d protein (PMID: 28646019). E233G results in homologous recombination-mediated DNA repair activity similar to wild-type Rad51d in cell culture (PMID: 28646019), but in another study, results in increased cell proliferation and telomere maintenance dysfunction in culture (PMID: 19033885), and therefore, its effect on Rad51d protein function is unknown.
RAD51D S207L missense loss of function RAD51D S207L lies within the Walker B motif of the Rad51d protein (PMID: 28646019). S207L results in impaired homologous recombination, as demonstrated by disruption of the interaction between Rad51d and Xrcc2 and decreased Rad50 accumulation in response to DNA damage in cultured cells (PMID: 28646019).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RAD51D S207L Advanced Solid Tumor sensitive Olaparib Preclinical - Cell culture Actionable In a preclinical study, cells expressing RAD51D S207L demonstrated decreased survival when treated with Lynparza (olaparib) in culture (PMID: 28646019). 28646019
RAD51D S207L Advanced Solid Tumor sensitive Talazoparib Preclinical - Cell culture Actionable In a preclinical study, cells expressing RAD51D S207L demonstrated decreased survival when treated with Talazoparib (BMN-673) in culture (PMID: 28646019). 28646019