Functionally Null RAD51D Missense Mutation Associates Strongly with Ovarian Carcinoma
Barbara Rivera,Massimo Di Iorio,Jessica Frankum,Javad Nadaf,Somayyeh Fahiminiya,Suzanna L. Arcand,David L. Burk,Damien Grapton,Eva Tomiak,Valerie Hastings,Nancy Hamel,Rabea Wagener,Olga Aleynikova,Sylvie Giroux,Fadi F. Hamdan,Alexandre Dionne-Laporte,George Zogopoulos,George Zogopoulos,François Rousseau,Albert M. Berghuis,Diane Provencher,Guy A. Rouleau,Jacques L. Michaud,Anne-Marie Mes-Masson,Jacek Majewski,Susanne Bens,Reiner Siebert,Steven A. Narod,Steven A. Narod,Mohammad R. Akbari,Mohammad R. Akbari,Christopher J. Lord,Patricia N. Tonin,Patricia N. Tonin,Alexandre Orthwein,William D. Foulkes +35 more
TLDR
Using deep sequencing and case-control genotyping studies, 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 RAD 51D variants.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 .read more
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Integrative Genomics Viewer
James T. Robinson,Helga Thorvaldsdottir,Wendy Winckler,Mitchell Guttman,Eric S. Lander,Eric S. Lander,Gad Getz,Jill P. Mesirov +7 more
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Journal ArticleDOI
RAD-ical New Insights into RAD51 Regulation.
TL;DR: The current perspective on the in vivo and in vitro function of the RAD51 paralogs is discussed, and their relationship with cancer in vertebrate models is discussed.
Journal ArticleDOI
Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D
Xin Yang,Honglin Song,Goska Leslie,Christoph Engel,Eric Hahnen,Bernd Auber,Judit Horvath,Karin Kast,Karin Kast,Karin Kast,Dieter Niederacher,Clare Turnbull,Richard S. Houlston,Helen Hanson,Chey Loveday,Jill S. Dolinsky,Holly LaDuca,Susan J. Ramus,Susan J. Ramus,Usha Menon,Adam N. Rosenthal,Ian Jacobs,Ian Jacobs,Ian Jacobs,Simon A. Gayther,Ed Dicks,Heli Nevanlinna,Kristiina Aittomäki,Liisa M. Pelttari,Hans Ehrencrona,Åke Borg,Anders Kvist,Barbara Rivera,Thomas Hansen,Malene Djursby,Andy C. H. Lee,Joe Dennis,David D.L. Bowtell,David D.L. Bowtell,Nadia Traficante,Nadia Traficante,Orland Diez,Judith Balmaña,Stephen B. Gruber,Georgia Chenevix-Trench,kConFab Investigators,Allan Jensen,Susanne K. Kjaer,Estrid Høgdall,Laurent Castera,Judy Garber,Ramunas Janavicius,Ana Osorio,Lisa Golmard,Ana Vega,Fergus J. Couch,Mark E. Robson,Jacek Gronwald,Susan M. Domchek,Julie O. Culver,Miguel de la Hoya,Douglas F. Easton,W. D. Foulkes,W. D. Foulkes,Marc Tischkowitz,Marc Tischkowitz,Alfons Meindl,Rita K. Schmutzler,Paul D.P. Pharoah,Antonis C. Antoniou +69 more
TL;DR: Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32–36% for TOC, for carriers with two first-degree relatives diagnosed with Toc, or 44–46% for BC, for carrier with two second-degree relative diagnosed with BC.
Journal ArticleDOI
Contribution of germline deleterious variants in the RAD51 paralogs to breast and ovarian cancers.
Lisa Golmard,Laurent Castera,Sophie Krieger,Sophie Krieger,Virginie Moncoutier,Khadija Abidallah,Henrique Tenreiro,Anthony Laugé,Julien Tarabeux,Gaël A. Millot,Gaël A. Millot,André Nicolas,Marick Laé,Caroline Abadie,Pascaline Berthet,Florence Polycarpe,Thierry Frebourg,Thierry Frebourg,Camille Elan,Antoine De Pauw,Marion Gauthier-Villars,Bruno Buecher,Marc-Henri Stern,Marc-Henri Stern,Dominique Stoppa-Lyonnet,Dominique Stoppa-Lyonnet,Dominique Vaur,Claude Houdayer,Claude Houdayer +28 more
TL;DR: This study is the first evaluation of the five RAD51 paralogs in breast and ovarian cancer predisposition and it demonstrates that deleterious variants can be present in breast cancer only cases.
Journal ArticleDOI
Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers
Wejdan M Alenezi,Caitlin T Fierheller,Caitlin T Fierheller,Neil Recio,Neil Recio,Patricia N. Tonin,Patricia N. Tonin +6 more
TL;DR: BARD1 is likely to be a low–moderate penetrance breast cancer risk gene, and the challenge of discovering additional cancer risk genes for hereditary breast and/or ovarian cancer has yet to be discovered.
References
More filters
Journal ArticleDOI
The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data
Aaron McKenna,Matthew Hanna,Eric Banks,Andrey Sivachenko,Kristian Cibulskis,Andrew Kernytsky,Kiran V. Garimella,David Altshuler,Stacey Gabriel,Mark J. Daly,Mark A. DePristo +10 more
TL;DR: The GATK programming framework enables developers and analysts to quickly and easily write efficient and robust NGS tools, many of which have already been incorporated into large-scale sequencing projects like the 1000 Genomes Project and The Cancer Genome Atlas.
Journal ArticleDOI
Integrative genomics viewer
James T. Robinson,Helga Thorvaldsdottir,Wendy Winckler,Mitchell Guttman,Eric S. Lander,Eric S. Lander,Gad Getz,Jill P. Mesirov +7 more
TL;DR: In this article, the authors present an approach for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Journal ArticleDOI
ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data
TL;DR: The ANNOVAR tool to annotate single nucleotide variants and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP is developed.
Journal ArticleDOI
Analysis of protein-coding genetic variation in 60,706 humans
Monkol Lek,Konrad J. Karczewski,Konrad J. Karczewski,Eric Vallabh Minikel,Eric Vallabh Minikel,Kaitlin E. Samocha,Eric Banks,Timothy Fennell,Anne H. O’Donnell-Luria,Anne H. O’Donnell-Luria,Anne H. O’Donnell-Luria,James S. Ware,Andrew J. Hill,Andrew J. Hill,Andrew J. Hill,Beryl B. Cummings,Beryl B. Cummings,Taru Tukiainen,Taru Tukiainen,Daniel P. Birnbaum,Jack A. Kosmicki,Laramie E. Duncan,Laramie E. Duncan,Karol Estrada,Karol Estrada,Fengmei Zhao,Fengmei Zhao,James Zou,Emma Pierce-Hoffman,Emma Pierce-Hoffman,Joanne Berghout,David Neil Cooper,Nicole A. Deflaux,Mark A. DePristo,Ron Do,Jason Flannick,Jason Flannick,Menachem Fromer,Laura D. Gauthier,Jackie Goldstein,Jackie Goldstein,Namrata Gupta,Daniel P. Howrigan,Daniel P. Howrigan,Adam Kiezun,Mitja I. Kurki,Mitja I. Kurki,Ami Levy Moonshine,Pradeep Natarajan,Lorena Orozco,Gina M. Peloso,Gina M. Peloso,Ryan Poplin,Manuel A. Rivas,Valentin Ruano-Rubio,Samuel A. Rose,Douglas M. Ruderfer,Khalid Shakir,Peter D. Stenson,Christine Stevens,Brett Thomas,Brett Thomas,Grace Tiao,María Teresa Tusié-Luna,Ben Weisburd,Hong-Hee Won,Dongmei Yu,David Altshuler,David Altshuler,Diego Ardissino,Michael Boehnke,John Danesh,Stacey Donnelly,Roberto Elosua,Jose C. Florez,Jose C. Florez,Stacey Gabriel,Gad Getz,Gad Getz,Stephen J. Glatt,Christina M. Hultman,Sekar Kathiresan,Markku Laakso,Steven A. McCarroll,Steven A. McCarroll,Mark I. McCarthy,Mark I. McCarthy,Dermot P.B. McGovern,Ruth McPherson,Benjamin M. Neale,Benjamin M. Neale,Aarno Palotie,Shaun Purcell,Danish Saleheen,Jeremiah M. Scharf,Pamela Sklar,Patrick F. Sullivan,Patrick F. Sullivan,Jaakko Tuomilehto,Ming T. Tsuang,Hugh Watkins,Hugh Watkins,James G. Wilson,Mark J. Daly,Mark J. Daly,Daniel G. MacArthur,Daniel G. MacArthur +106 more
TL;DR: The aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC) provides direct evidence for the presence of widespread mutational recurrence.
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