Fine-Scale Mapping at 9p22.2 Identifies Candidate Causal Variants That Modify Ovarian Cancer Risk in BRCA1 and BRCA2 Mutation Carriers.

Authors:
Elena Vigorito Karoline B Kuchenbaecker Jonathan Beesley Julian Adlard Bjarni A Agnarsson Irene L Andrulis Banu K Arun Laure Barjhoux Muriel Belotti Javier Benitez Andreas Berger Anders Bojesen Bernardo Bonanni Carole Brewer Trinidad Caldes Maria A Caligo Ian Campbell Salina B Chan Kathleen B M Claes David E Cohn Jackie Cook Mary B Daly Francesca Damiola Rosemarie Davidson Antoine de Pauw Capucine Delnatte Orland Diez Susan M Domchek Martine Dumont Katarzyna Durda Bernd Dworniczak Douglas F Easton Diana Eccles Christina Edwinsdotter Ardnor Ros Eeles Bent Ejlertsen Steve Ellis D Gareth Evans Lidia Feliubadalo Florentia Fostira William D Foulkes Eitan Friedman Debra Frost Pragna Gaddam Patricia A Ganz Judy Garber Vanesa Garcia-Barberan Marion Gauthier-Villars Andrea Gehrig Anne-Marie Gerdes Sophie Giraud Andrew K Godwin David E Goldgar Christopher R Hake Thomas V O Hansen Sue Healey Shirley Hodgson Frans B L Hogervorst Claude Houdayer Peter J Hulick Evgeny N Imyanitov Claudine Isaacs Louise Izatt Angel Izquierdo Lauren Jacobs Anna Jakubowska Ramunas Janavicius Katarzyna Jaworska-Bieniek Uffe Birk Jensen Esther M John Joseph Vijai Beth Y Karlan Karin Kast KConFab Investigators Sofia Khan Ava Kwong Yael Laitman Jenny Lester Fabienne Lesueur Annelie Liljegren Jan Lubinski Phuong L Mai Siranoush Manoukian Sylvie Mazoyer Alfons Meindl Arjen R Mensenkamp Marco Montagna Katherine L Nathanson Susan L Neuhausen Heli Nevanlinna Dieter Niederacher Edith Olah Olufunmilayo I Olopade Kai-Ren Ong Ana Osorio Sue Kyung Park Ylva Paulsson-Karlsson Inge Sokilde Pedersen Bernard Peissel Paolo Peterlongo Georg Pfeiler Catherine M Phelan Marion Piedmonte Bruce Poppe Miquel Angel Pujana Paolo Radice Gad Rennert Gustavo C Rodriguez Matti A Rookus Eric A Ross Rita Katharina Schmutzler Jacques Simard Christian F Singer Thomas P Slavin Penny Soucy Melissa Southey Doris Steinemann Dominique Stoppa-Lyonnet Grzegorz Sukiennicki Christian Sutter Csilla I Szabo Muy-Kheng Tea Manuel R Teixeira Soo-Hwang Teo Mary Beth Terry Mads Thomassen Maria Grazia Tibiletti Laima Tihomirova Silvia Tognazzo Elizabeth J van Rensburg Liliana Varesco Raymonda Varon-Mateeva Athanassios Vratimos Jeffrey N Weitzel Lesley McGuffog Judy Kirk Amanda Ewart Toland Ute Hamann Noralane Lindor Susan J Ramus Mark H Greene Fergus J Couch Kenneth Offit Paul D P Pharoah Georgia Chenevix-Trench Antonis C Antoniou

PLoS One 2016 27;11(7):e0158801. Epub 2016 Jul 27.

Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158801PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4963094PMC

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July 2017
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