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

kConFab Investigators

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Abstrakt

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.

OriginalsprogEngelsk
Artikelnummere0158801
TidsskriftPLOS ONE
Vol/bind11
Udgave nummer7
Antal sider19
ISSN1932-6203
DOI
StatusUdgivet - 1. jan. 2016

Bibliografisk note

ISI Document Delivery No.: DT5IJ Times Cited: 0 Cited Reference Count: 21 Vigorito, Elena Kuchenbaecker, Karoline B. Beesley, Jonathan Adlard, Julian Agnarsson, Bjarni A. Andrulis, Irene L. Arun, Banu K. Barjhoux, Laure Belotti, Muriel Benitez, Javier Berger, Andreas Bojesen, Anders Bonanni, Bernardo Brewer, Carole Caldes, Trinidad Caligo, Maria A. Campbell, Ian Chan, Salina B. Claes, Kathleen B. M. Cohn, David E. Cook, Jackie Daly, Mary B. Damiola, Francesca Davidson, Rosemarie de Pauw, Antoine Delnatte, Capucine Diez, Orland Domchek, Susan M. Dumont, Martine Durda, Katarzyna Dworniczak, Bernd Easton, Douglas F. Eccles, Diana Ardnor, Christina Edwinsdotter Eeles, Ros Ejlertsen, Bent Ellis, Steve Evans, D. Gareth Feliubadalo, Lidia Fostira, Florentia Foulkes, William D. Friedman, Eitan Frost, Debra Gaddam, Pragna Ganz, Patricia A. Garber, Judy Garcia-Barberan, Vanesa Gauthier-Villars, Marion Gehrig, Andrea Gerdes, Anne-Marie Giraud, Sophie Godwin, Andrew K. Goldgar, David E. Hake, Christopher R. Hansen, Thomas V. O. Healey, Sue Hodgson, Shirley Hogervorst, Frans B. L. Houdayer, Claude Hulick, Peter J. Imyanitov, Evgeny N. Isaacs, Claudine Izatt, Louise Izquierdo, Angel Jacobs, Lauren Jakubowska, Anna Janavicius, Ramunas Jaworska-Bieniek, Katarzyna Jensen, Uffe Birk John, Esther M. Vijai, Joseph Karlan, Beth Y. Kast, Karin Khan, Sofia Kwong, Ava Laitman, Yael Lester, Jenny Lesueur, Fabienne Liljegren, Annelie Lubinski, Jan Mai, Phuong L. Manoukian, Siranoush Mazoyer, Sylvie Meindl, Alfons Mensenkamp, Arjen R. Montagna, Marco Nathanson, Katherine L. Neuhausen, Susan L. Nevanlinna, Heli Niederacher, Dieter Olah, Edith Olopade, Olufunmilayo I. Ong, Kai-ren Osorio, Ana Park, Sue Kyung Paulsson-Karlsson, Ylva Pedersen, Inge Sokilde Peissel, Bernard Peterlongo, Paolo Pfeiler, Georg Phelan, Catherine M. Piedmonte, Marion Poppe, Bruce Angel Pujana, Miquel Radice, Paolo Rennert, Gad Rodriguez, Gustavo C. Rookus, Matti A. Ross, Eric A. Schmutzler, Rita Katharina Simard, Jacques Singer, Christian F. Slavin, Thomas P. Soucy, Penny Southey, Melissa Steinemann, Doris Stoppa-Lyonnet, Dominique Sukiennicki, Grzegorz Sutter, Christian Szabo, Csilla I. Tea, Muy-Kheng Teixeira, Manuel R. Teo, Soo-Hwang Terry, Mary Beth Thomassen, Mads Tibiletti, Maria Grazia Tihomirova, Laima Tognazzo, Silvia van Rensburg, Elizabeth J. Varesco, Liliana Varon-Mateeva, Raymonda Vratimos, Athanassios Weitzel, Jeffrey N. McGuffog, Lesley Kirk, Judy Toland, Amanda Ewart Hamann, Ute Lindor, Noralane Ramus, Susan J. Greene, Mark H. Couch, Fergus J. Offit, Kenneth Pharoah, Paul D. P. Chenevix-Trench, Georgia Antoniou, Antonis C. Osorio, Ana/I-4324-2014; Teo, Soo-hwang/H-2353-2014; Jansen van Rensburg, Elizabeth (Lizette)/B-9104-2011; Osorio, Ana/0000-0001-8124-3984; Khan, Sofia/0000-0003-4185-8882; Evans, Gareth/0000-0002-8482-5784 Cancer Research - UK [C12292/A11174, C1287/A10118]; MRC Advanced Studentship award; NHMRC; National Breast Cancer Foundation; Cancer Australia; National Institute of Health (USA) The CIMBA data management and data analysis were supported by Cancer Research - UK grants C12292/A11174 and C1287/A10118. EV was supported by an MRC Advanced Studentship award. Details of the funding of individual studies participating in CIMBA are included in S1 Text of the manuscript.; BCFR-AU acknowledges Maggie Angelakos, Judi Maskiell, Gillian Dite, Helen Tsimiklis. BCFR-NY wishes to thank members and participants in the New York site of the Breast Cancer Family Registry for their contributions to the study. BCFR-ON wishes to thank members and participants in the Ontario Familial Breast Cancer Registry for their contributions to the study. BFBOCC-LT acknowledges Vilius Rudaitis, Laimonas Grigkeviequs. BMBSA We wish to thank the families who contribute to the BMBSA study. BRICOH wishes to thank Yuan Chun Ding and Linda Steele for their work in participant enrollment and biospecimen and data management. CBCS thanks Bent Ejlertsen for the recruitment and genetic counseling of participants. CNIO thanks Alicia Barroso, Rosario Alonso and Guillermo Pita for their assistance. CONSIT TEAM acknowledges Daniela Zaffaroni of the Fondazione IRCCS Istituto Nazionale deti Tumori, Milano, Italy: Monica Barile and Irene Feroce of the Istituto Europeo di Oncologia, Milano, Italy; Alessandra Viel and Riccardo Dolcetti of the CRO Aviano National Cancer Institute, Aviano (PN), Italy; Laura Papi and Gabriele Capone of the University of Florence, Florence, Italy; Laura Ottini and Giuseppe Giannini of the "Sapienza" University, Rome, Italy; Antonella Savarese and Alyne Martayan of the Istituto Nazionale Tumori Regina Elena, Rome, Italy; Stefania Tommasi of the Istituto Nazionale Tumori "Giovanni Paolo II" Bari, Italy. GCHBOC thanks Ms. JoEllen Weaver and Dr. Betsy Bove for their technical support. GEMO wishes to pay a tribute to Olga M. Sinilnikova, who with Dominique Stoppa-Lyonnet initiated and coordinated GEMO until she sadly passed away on the 30th June 2014, and to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unite Mixte de Genetique Constitutionnelle des Cancers Frequents, Hospices Civils de Lyon Centre Leon Berard, & Equipe Genetique du cancer du sein, Centre de Recherche en Cancerologie de Lyon: Olga Sinilnikovat, Sylvie Mazoyer, Francesca Damiola, Laure Barjhoux, Carole Verny-Pierre, Melanie Leone, Nadia Boutry-Kryza, Alain Calender, Sophie Giraud; and Service de Genetique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Etienne Rouleau, Lisa Golmard, Agnes Collet, Virginie Moncoutier, Muriel Belotti, Antoine de Pauw, Camille Elan, Catherine Nogues, Emmanuelle Fourme, Anne -Marie Birot. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Olivier Caron, Marine Guillaud-Bataille. Centre Jean Perrin, Clermont-Ferrand: Yves -Jean Bignon, Nancy Uhrhammer. Centre Leon Berard, Lyon: Christine Lasset, Valerie Bonadona, Sandrine Handallou. Centre Francois Baclesse, Caen: Agnes Hardouin, Pascaline Berthet, Dominique Vaur, Laurent Castera. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Audrey Remenieras, Francois Eisinger. CHU Arnaud -de -Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean -Philippe Peyrat, Joelle Fournier, Francoise Revillion, Philippe Vennint, Claude Adenis. Centre Paul Strauss, Strasbourg: Daniele Muller, Jean-Pierre Fricker. Institut Bergonie, Bordeaux: Emmanuelle Barouk-Simonet, Francoise Bonnet, Virginie Bubien, Nicolas Sevenet, Michel Longy. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU Grenoble: Dominique Leroux, Helene Dreyfus, Christine Rebischung, Magalie Peysselon.; CHU Dijon: Fanny Coron, Laurence Faivre. CHU St -Etienne: Fabienne Prieur, Marine Lebrun, Caroline Kientz. Hotel Dieu Centre Hospitalier, Chambery: Sandra Fert Ferrer. Centre Antoine Lacassagne, Nice: Marc Frenay. CHU Limoges: Laurence Venat-Bouvet. CHU Nantes: Capucine Delnatte. CHU Bretonneau, Tours: Isabelle Mortemousque. Groupe Hospitalier Pitie-Salpetriere, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier, Mathilde Warcoin. CHU Vandoeuvre-les-Nancy: Johanna Sokolowska, Myriam Bronner. CHU Besancon: Marie -Agnes Collonge-Rame, Alexandre Damette. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L. Snyder. HCSC acknowledges Alicia Tosar and Paula Diaque for their technical assistance. HEBCS would like to thank Dr. Kristiina Aittomaki, Taru A. Muranen, Drs. Carl Blomqvist and Kirsimari Aaltonen and RNs Irja Erkkila and Virpi Palola for their help with the HEBCS data and samples. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) consists of the following Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: M.A. Rookus, F.B.L. Hogervorst, F.E. van Leeuwen, S. Verhoef, M.K. Schmidt, N.S. Russell, J.L. de Lange, R. Wijnands; Erasmus Medical Center, Rotterdam, NL: J.M. Collee, A.M.W. van den Ouweland, M.J. Hooning, C. Seynaeve, C.H.M. van Deurzen, I.M. Obdeijn; Leiden University Medical Center, NL: C. J. van Asperen, J.T. Wijnen, R.A.E.M. Tollenaar, P. Devilee, T.C.T.E.F. van Cronenburg; Radboud University Nijmegen Medical Center, NL: C.M. Kets, A.R. Mensenkamp; University Medical Center Utrecht, NL: M.G.E.M. Ausems, R.B. van der Luijt, C.C. van der Pol; Amsterdam Medical Center, NL: C.M. Aalfs, T.A.M. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, NL: E.B. Gomez -Garcia, M.J. Blok; University Medical Center Groningen, NL: J.C. Oosterwijk, A. H. van der Hout, M.J. Mourits, G.H. de Bock; The Netherlands Foundation for the detection of hereditary tumours, Leiden, NL: H.F. Vasen; The Netherlands Comprehensive Cancer Organization (IKNL): S. Siesling, J.Verloop; The Dutch Pathology Registry (PALGA): L.I.H. Overbeek. HEBON thanks the registration teams of IKNL and PALGA for part of the data collection. HRBCP wishes to thank Hong Kong Sanatorium and Hospital for their continued support. HUNBOCS wishes to thank the Hungarian Breast and Ovarian Cancer Study Group members (Janos Papp, Tibor Vaszko, Aniko Bozsik, Timea Pocza, Judit Franko, Maria Balogh, Gabriella Domokos, Judit Ferenczi, Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary) and the clinicians and patients for their contributions to this study. ICO wishes to thank the ICO Hereditary Cancer Program team led by Dr. Gabriel Capella. INHERIT would like to thank Dr Martine Dumont, Martine Tranchant for sample management and skilful technical assistance. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. J.S. and P.S. were part of the QC and Genotyping coordinating group of iCOGS (BCAC and CIMBA). IPOBCS wishes to thank Drs. Ana Peixoto, Catarina Santos, Patricia Rocha and Pedro Pinto for their skilful contribution to the study.; KCONFAB wishes to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, and the Clinical Follow Up Study (which has received funding from the NHMRC, the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health (USA)) for their contributions to this resource, and the many families who contribute to kConFab. MCGILL Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. MODSQUAD acknowledges ModSQuaD members Csilla Szabo (National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA); Lenka Foretova and Eva Machackova (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno, Czech Republic); and Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Oncogynecologic Center and Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic). NICCC wishes to thank the NICCC National Familial Cancer Consultation Service team led by Sara Dishon, the lab team led by Dr. Flavio Lejbkowicz, and the research field operations team led by Dr. Mila Pinchev. OCGN We wish to thank members and participants in the Ontario Cancer Genetics Network for their contributions to the study. OSU CCG Leigha Senter, Kevin Sweet, Caroline Craven, and Michelle O'Conor were instrumental in accrual of study participants, ascertainment of medical records and database management. Samples were processed by the OSU Human Genetics Sample Bank. SEABASS would like to thank Yip Cheng Har, Nur Aishah Mohd Taib, Phuah Sze Yee, Norhashimah Hassan and all the research nurses, research assistants and doctors involved in the MyBrCa Study for assistance in patient recruitment, data collection and sample preparation. In addition, we thank Philip Iau, Sng Jen-Hwei and Sharifah Nor Akmal for contributing samples from the Singapore Breast Cancer Study and the HUKM-HKL Study respectively. SMC team wishes to acknowledge the assistance of the Meirav Comprehensive breast cancer center team at the Sheba Medical Center for assistance in this study. SWE-BRCA Swedish scientists participating as SWE-BRCA collaborators are: from Lund University and University Hospital: Ake Borg, Hakan Olsson, Helena Jernstrom, Karin Henriksson, Katja Harbst, Maria Soller, Ulf Kristoffersson; from Gothenburg Sahlgrenska University Hospital: Anna Ofverholm, Margareta Nordling, Per Karlsson, Zakaria Einbeigi; from Stockholm and Karolinska University Hospital: Anna von Wachenfeldt, Annelie Liljegren, Annika Lindblom, Brita Arver, Gisela Barbany Bustinza, Johanna Rantala; from Ume5. University Hospital: Beatrice Melin, Christina Edwinsdotter Ardnor, Monica Emanuelsson; from Uppsala University: Hans Ehrencrona, Maritta Hellstrom Pigg, Richard Rosenquist; from Linkoping University Hospital: Marie Stenmark-Askmalm, Sigrun Liedgren. UCHICAGO wishes to thank Cecilia Zvocec, Qun Niu, physicians, genetic counselors, research nurses and staff of the Cancer Risk Clinic for their contributions to this resource, and the many families who contribute to our program. UCLA thanks Joyce Seldon MSGC and Lorna Kwan, MPH for assembling the data for this study. UCSF would like to thank Dr Robert Nussbaum and the following genetic counsellors for participant recruitment: Beth Crawford, Kate Loranger, Julie Mak, Nicola Stewart, Robin Lee, Amie Blanco and Peggy Conrad. And thanks to Ms. Salina Chan for her data management.; UKFOCR thanks Simon Gayther, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR. UPENN Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. VFCTG acknowledges Geoffrey Lindeman, Marion Harris, Martin Delatycki of the Victorian Familial Cancer Trials Group. We thank Sarah Sawyer and Rebecca Driessen for assembling this data and Ella Thompson for performing all DNA amplification 0 8 Public library science San francisco

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