Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Fergus J. Couch; Xianshu Wang; Lesley McGuffog; Andrew Lee; Curtis Olswold; Karoline B. Kuchenbaecker; Penny Soucy; Zachary Fredericksen; Daniel Barrowdale; Joe Dennis; Mia M. Gaudet; Ed Dicks; Matthew Kosel; Sue Healey; Olga M. Sinilnikova; Adam Lee; Francois Bacot; Daniel Vincent; Frans B. L. Hogervorst; Susan Peock; Dominique Stoppa-Lyonnet; Anna Jakubowska; Paolo Radice; Rita Katharina Schmutzler; Susan M. Domchek; Marion Piedmonte; Christian F. Singer; Eitan Friedman; Mads Thomassen; Thomas V. O. Hansen; Susan L. Neuhausen; Csilla I. Szabo; Ignacio Blanco; Mark H. Greene; Beth Y. Karlan; Judy Garber; Catherine M. Phelan; Jeffrey N. Weitzel; Marco Montagna; Edith Olah; Irene L. Andrulis; Andrew K. Godwin; Drakoulis Yannoukakos; David E. Goldgar; Trinidad Caldes; Heli Nevanlinna; Ana Osorio; Mary Beth Terry; Mary B. Daly; Elizabeth J. van Rensburg; Ute Hamann; Susan J. Ramus; Amanda Ewart Toland; Maria A. Caligo; Olufunmilayo I. Olopade; Nadine Tung; Kathleen Claes; Mary S. Beattie; Melissa C. Southey; Evgeny N. Imyanitov; Marc Tischkowitz; Ramunas Janavicius; Esther M. John; Ava Kwong; Orland Diez; Judith Balmana; Rosa B. Barkardottir; Banu K. Arun; Gad Rennert; Soo-Hwang Teo; Patricia A. Ganz; Ian Campbell; Annemarie H. van der Hout; Carolien H. M. van Deurzen; Caroline Seynaeve; Encarna B. Gomez Garcia; Flora E. van Leeuwen; Hanne E. J. Meijers-Heijboer; Johannes J. P. Gille; Margreet G. E. M. Ausems; Marinus J. Blok; Marjolijn J. L. Ligtenberg; Matti A. Rookus; Peter Devilee; Senno Verhoef; Theo A. M. van Os; Juul T. Wijnen; Debra Frost; Steve Ellis; Elena Fineberg; Radka Platte; D. Gareth Evans; Louise Izatt; Rosalind A. Eeles; Julian Adlard; Diana M. Eccles; Jackie Cook; Carole Brewer; Fiona Douglas; Shirley Hodgson; KConFab Investigators; Christine June Jacobs

doi:10.1371/journal.pgen.1003212

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Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

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Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Fergus J. Couch, Xianshu Wang, Lesley McGuffog, Andrew Lee, Curtis Olswold, Karoline B. Kuchenbaecker, Penny Soucy, Zachary Fredericksen, Daniel Barrowdale, Joe Dennis, …

PLoS genetics, Vol.9(3), pp.e1003212-e1003212

2013

DOI: https://doi.org/10.1371/journal.pgen.1003212

PMID: 23544013

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

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Title: Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
Creators: Fergus J. Couch - Mayo Clinic in Florida
Xianshu Wang - Mayo Clinic
Lesley McGuffog - University of Cambridge
Andrew Lee - University of Cambridge
Curtis Olswold - Mayo Clinic in Florida
Karoline B. Kuchenbaecker - University of Cambridge
Penny Soucy - Centre hospitalier universitaire de Québec
Zachary Fredericksen - Mayo Clinic in Florida
Daniel Barrowdale - University of Cambridge
Joe Dennis - University of Cambridge
Mia M. Gaudet - American Cancer Society
Ed Dicks - University of Cambridge
Matthew Kosel - Mayo Clinic in Florida
Sue Healey - QIMR Berghofer Medical Research Institute
Olga M. Sinilnikova - Centre de Recherche en Cancérologie de Lyon
Adam Lee - Mayo Clinic
Francois Bacot - McGill University
Daniel Vincent - McGill University
Frans B. L. Hogervorst - The Netherlands Cancer Institute
Susan Peock - University of Cambridge
Dominique Stoppa-Lyonnet - Institut Curie
Anna Jakubowska - Pomeranian Medical University
Paolo Radice - FIRC Institute of Molecular Oncology
Rita Katharina Schmutzler - University Hospital Cologne
Susan M. Domchek - University of Pennsylvania
Marion Piedmonte - Gynecologic Oncology Group
Christian F. Singer - Comprehensive Cancer Center Vienna
Eitan Friedman - Sheba Medical Center
Mads Thomassen - Odense University Hospital
Thomas V. O. Hansen - College Station Medical Center
Susan L. Neuhausen - City of Hope
Csilla I. Szabo - University of Delaware
Ignacio Blanco - Institut Català d'Oncologia
Mark H. Greene - National Cancer Institute
Beth Y. Karlan - Cedars-Sinai Medical Center
Judy Garber - Dana-Farber Cancer Institute
Catherine M. Phelan - Moffitt Cancer Center
Jeffrey N. Weitzel - City of Hope
Marco Montagna - Istituto Oncologico Veneto
Edith Olah - National Institute of Oncology
Irene L. Andrulis - Mount Sinai Hospital
Andrew K. Godwin - University of Kansas Medical Center
Drakoulis Yannoukakos - National Centre of Scientific Research "Demokritos"
David E. Goldgar - University of Utah
Trinidad Caldes - Hospital Clínico San Carlos
Heli Nevanlinna - Helsinki University Hospital
Ana Osorio - Spanish National Cancer Research Centre
Mary Beth Terry - Columbia University
Mary B. Daly - Fox Chase Cancer Center
Elizabeth J. van Rensburg - University of Pretoria
Ute Hamann - DKFZ-ZMBH Alliance
Susan J. Ramus - University of Southern California
Amanda Ewart Toland - The Ohio State University
Maria A. Caligo - Azienda Ospedaliera Universitaria Pisana
Olufunmilayo I. Olopade - Cancer Genetics
Nadine Tung - Beth Israel Deaconess Medical Center
Kathleen Claes - Ghent University Hospital
Mary S. Beattie - University of California, San Francisco
Melissa C. Southey - University of Melbourne
Evgeny N. Imyanitov - Institute of Oncology NN Petrov
Marc Tischkowitz - McGill University
Ramunas Janavicius - Vilnius University
Esther M. John - Cancer Prevention Institute of California
Ava Kwong - Hong Kong Sanatorium and Hospital
Orland Diez - Univ Hosp Vall dHebron, Oncogenet Lab, Barcelona, Spain
Judith Balmana - Vall d'Hebron Hospital Universitari
Rosa B. Barkardottir - University of Iceland
Banu K. Arun - The University of Texas MD Anderson Cancer Center
Gad Rennert - Carmel Medical Center
Soo-Hwang Teo - Univ Malaya, Canc Res Initiat Fdn, Sime Darby Med Ctr, Kuala Lumpur, Malaysia
Patricia A. Ganz - Supreme Council Of Health
Ian Campbell - Peter MacCallum Cancer Centre
Annemarie H. van der Hout - University Medical Center Groningen
Carolien H. M. van Deurzen - Erasmus MC
Caroline Seynaeve - Erasmus MC
Encarna B. Gomez Garcia - Supreme Council Of Health
Flora E. van Leeuwen - Oncode Institute
Hanne E. J. Meijers-Heijboer - University of Amsterdam
Johannes J. P. Gille - University of Amsterdam
Margreet G. E. M. Ausems - University Medical Center Utrecht
Marinus J. Blok - Maastricht University
Marjolijn J. L. Ligtenberg - Radboud University Nijmegen
Matti A. Rookus - Oncode Institute
Peter Devilee - Leiden University Medical Center
Senno Verhoef - The Netherlands Cancer Institute
Theo A. M. van Os - Academic Medical Center
Juul T. Wijnen - Leiden University Medical Center
Debra Frost - University of Cambridge
Steve Ellis
Elena Fineberg - University of Cambridge
Radka Platte - University of Cambridge
D. Gareth Evans - Manchester Academic Health Science Centre
Louise Izatt - Guy's and St Thomas' NHS Foundation Trust
Rosalind A. Eeles - Royal Marsden NHS Foundation Trust
Julian Adlard - Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England
Diana M. Eccles - University of Southampton
Jackie Cook - Sheffield Children's Hospital
Carole Brewer - Royal Devon and Exeter Hospital
Fiona Douglas - Centre for Life
Shirley Hodgson - St George's, University of London
KConFab Investigators
Christine June Jacobs - School of Health Sciences
Publication Details: PLoS genetics, Vol.9(3), pp.e1003212-e1003212
Publisher: Public Library Science
Number of pages: 21
Date published: 2013
Grant note: 132473 / Academy of Finland; Research Council of Finland Israel Cancer Association LIG-19/2010 / Research Council of Lithuania; Research Council of Lithuania (LMTLT) Hereditary Cancer Association (Paveldimo vezio asociacija) IG 8713 / Italian Association for Cancer Research (AIRC); Fondazione AIRC per la ricerca sul cancro NHMRC; National Health & Medical Research Council (NHMRC) of Australia University of Kansas Cancer Center Association "Le cancer du sein, parlons-en!" Catalan Health Institute National Health and Medical Research Council (NHMRC); National Health & Medical Research Council (NHMRC) of Australia
Identifiers: 99928840702346
Academic Unit: School of Health Sciences
Language: English
Resource Type: Journal article

Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

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