Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

David G. Cox; Christine June Jacobs; Jacques Simard; Daniel Sinnett; Yosr Hamdi; Penny Soucy; Manon Ouimet; Laure Barjhoux; Carole Verny-Pierre; Lesley McGuffog; Sue Healey; Csilla Szabo; Mark H. Greene; Phuong L. Mai; Irene L. Andrulis; Mads Thomassen; Anne-Marie Gerdes; Maria A. Caligo; Eitan Friedman; Yael Laitman; Bella Kaufman; Shani S. Paluch; Ake Borg; Per Karlsson; Marie Stenmark Askmalm; Gisela Barbany Bustinza; Katherine L. Nathanson; Susan M. Domchek; Timothy R. Rebbeck; Javier Benitez; Ute Hamann; Matti A. Rookus; Ans M. W. van den Ouweland; Margreet G. E. M. Ausems; Cora M. Aalfs; Christi J. van Asperen; Peter Devilee; Hans J. J. P. Gille; Susan Peock; Debra Frost; D. Gareth Evans; Ros Eeles; Louise Izatt; Julian Adlard; Joan Paterson; Jacqueline Eason; Andrew K. Godwin; Marie-Alice Remon; Virginie Moncoutier; Marion Gauthier-Villars; Christine Lasset; Sophie Giraud; Agnes Hardouin; Pascaline Berthet; Hagay Sobol; Francois Eisinger; Brigitte Bressac de Paillerets; Olivier Caron; Capucine Delnatte; David Goldgar; Alex Miron; Hilmi Ozcelik; Saundra Buys; Melissa C. Southey; Mary Beth Terry; Christian F. Singer; Anne-Catharina Dressler; Muy-Kheng Tea; Thomas V. O. Hansen; Oskar Johannsson; Marion Piedmonte; Gustavo C. Rodriguez; Jack B. Basil; Stephanie Blank; Amanda E. Toland; Marco Montagna; Claudine Isaacs; Ignacio Blanco; Simon A. Gayther; Kirsten B. Moysich; Rita K. Schmutzler; Barbara Wappenschmidt; Christoph Engel; Alfons Meindl; Nina Ditsch; Norbert Arnold; Dieter Niederacher; Christian Sutter; Dorothea Gadzicki; Britta Fiebig; Trinidad Caldes; Rachel Laframboise; Heli Nevanlinna; Xiaoqing Chen; Jonathan Beesley; Amanda B. Spurdle; Susan L. Neuhausen; Yuan C. Ding; Fergus J. Couch; Xianshu Wang; Paolo Peterlongo; Siranoush Manoukian; Loris Bernard; Paolo Radice; Douglas F. Easton; Georgia Chenevix-Trench; Antonis C. Antoniou; Dominique Stoppa-Lyonnet; Sylvie Mazoyer; Olga M. Sinilnikova; Ontario Canc Genetics Network

doi:10.1093/hmg/ddr388

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Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

Journal article

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Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

David G. Cox, Christine June Jacobs, Jacques Simard, Daniel Sinnett, Yosr Hamdi, Penny Soucy, Manon Ouimet, Laure Barjhoux, Carole Verny-Pierre, Lesley McGuffog, …

Human molecular genetics, Vol.20(23), pp.4732-4747

01/12/2011

DOI: https://doi.org/10.1093/hmg/ddr388

PMCID: PMC3733139

PMID: 21890493

Abstract

Biochemistry & Molecular Biology

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P = 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

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Title: Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers
Creators: David G. Cox - Cancer Research Center of Lyon
Christine June Jacobs - School of Health Sciences
Jacques Simard - Centre Hospitalier Universitaire de Québec
Daniel Sinnett - Centre Hospitalier Universitaire Sainte-Justine
Yosr Hamdi - Centre Hospitalier Universitaire de Québec
Penny Soucy - Centre Hospitalier Universitaire de Québec
Manon Ouimet - Centre Hospitalier Universitaire Sainte-Justine
Laure Barjhoux - Cancer Research Center of Lyon
Carole Verny-Pierre - Cancer Research Center of Lyon
Lesley McGuffog - University of Cambridge
Sue Healey - QIMR Berghofer Medical Research Institute
Csilla Szabo - University of Delaware
Mark H. Greene - National Cancer Institute
Phuong L. Mai - US Natl Canc Inst, Clin Genet Branch, Rockville, MD USA
Irene L. Andrulis - University of Toronto
Mads Thomassen - Odense University Hospital
Anne-Marie Gerdes - Copenhagen Univ Hosp, Dept Clin Genet, Copenhagen, Denmark
Maria A. Caligo - Azienda Ospedaliera Universitaria Pisana
Eitan Friedman - Tel Aviv University
Yael Laitman - College Station Medical Center
Bella Kaufman - Sheba Medical Center
Shani S. Paluch - Tel Aviv University
Ake Borg - Lund University
Per Karlsson - Sahlgrenska University Hospital
Marie Stenmark Askmalm - Linköping University Hospital
Gisela Barbany Bustinza - Karolinska University Hospital
Katherine L. Nathanson - University of Pennsylvania
Susan M. Domchek - University of Pennsylvania
Timothy R. Rebbeck - University of Pennsylvania
Javier Benitez - Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Human Genet Grp & Genotyping Unit, Madrid, Spain
Ute Hamann - DKFZ-ZMBH Alliance
Matti A. Rookus - Oncode Institute
Ans M. W. van den Ouweland - Erasmus MC
Margreet G. E. M. Ausems - University Medical Center Utrecht
Cora M. Aalfs - Academic Medical Center
Christi J. van Asperen - Leiden University
Peter Devilee - Leiden University Medical Center
Hans J. J. P. Gille - University of Amsterdam
Susan Peock - University of Cambridge
Debra Frost - University of Cambridge
D. Gareth Evans - Manchester Academic Health Science Centre
Ros Eeles - Inst Canc Res, Oncogenet Team, Surrey, England
Louise Izatt - Guy's and St Thomas' NHS Foundation Trust
Julian Adlard - Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England
Joan Paterson - Addenbrooke's Hospital
Jacqueline Eason - Nottingham University Hospitals NHS Trust
Andrew K. Godwin - Fox Chase Cancer Center
Marie-Alice Remon - Institute Curie
Virginie Moncoutier - Institute Curie
Marion Gauthier-Villars - Institute Curie
Christine Lasset - Claude Bernard University Lyon 1
Sophie Giraud - Centre Léon Bérard
Agnes Hardouin - Centre François Baclesse
Pascaline Berthet - Centre François Baclesse
Hagay Sobol - Inserm
Francois Eisinger - Institute Paoli-Calmettes
Brigitte Bressac de Paillerets - Inst Cancerol Gustave Roussy, Dept Genet, Villejuif, France
Olivier Caron - Institut Gustave Roussy
Capucine Delnatte - Centre Hospitalier René-Dubos
David Goldgar - University of Utah
Alex Miron - Dana-Farber Cancer Institute
Hilmi Ozcelik - Mount Sinai Hospital
Saundra Buys - Huntsman Cancer Institute
Melissa C. Southey - University of Melbourne
Mary Beth Terry - Columbia University
Christian F. Singer - Comprehensive Cancer Center Vienna
Anne-Catharina Dressler - Comprehensive Cancer Center Vienna
Muy-Kheng Tea - University of Vienna
Thomas V. O. Hansen - College Station Medical Center
Oskar Johannsson - University of Iceland
Marion Piedmonte - Roswell Pk Canc Inst, Stat & Data Ctr, Buffalo, NY 14263 USA
Gustavo C. Rodriguez - NorthShore University HealthSystem
Jack B. Basil - Good Samaritan Hospital
Stephanie Blank - New York University
Amanda E. Toland - The Ohio State University
Marco Montagna - Istituto Oncologico Veneto
Claudine Isaacs - Georgetown University Medical Center
Ignacio Blanco - Institut Català d'Oncologia
Simon A. Gayther - University of Southern California
Kirsten B. Moysich - Roswell Park Cancer Institute
Rita K. Schmutzler - University Hospital Cologne
Barbara Wappenschmidt - University Hospital Cologne
Christoph Engel - Leipzig University
Alfons Meindl - Rechts der Isar Hospital
Nina Ditsch - Ludwig-Maximilians-Universität München
Norbert Arnold - Kiel University
Dieter Niederacher - Heinrich Heine University Düsseldorf
Christian Sutter - Heidelberg University
Dorothea Gadzicki - Medizinische Hochschule Hannover
Britta Fiebig - University of Regensburg
Trinidad Caldes - Hospital Clínico San Carlos
Rachel Laframboise - Centre Hospitalier Universitaire de Québec
Heli Nevanlinna - Helsinki University Hospital
Xiaoqing Chen - QIMR Berghofer Medical Research Institute
Jonathan Beesley - QIMR Berghofer Medical Research Institute
Amanda B. Spurdle - QIMR Berghofer Medical Research Institute
Susan L. Neuhausen - City of Hope
Yuan C. Ding - City of Hope
Fergus J. Couch - Mayo Clinic in Arizona
Xianshu Wang - Mayo Clinic in Arizona
Paolo Peterlongo - Genetic Analysis
Siranoush Manoukian - Fondazione IRCCS Istituto Nazionale dei Tumori
Loris Bernard - European Institute of Oncology
Paolo Radice - Genetic Analysis
Douglas F. Easton - University of Cambridge
Georgia Chenevix-Trench - QIMR Berghofer Medical Research Institute
Antonis C. Antoniou - University of Cambridge
Dominique Stoppa-Lyonnet - Institute Curie
Sylvie Mazoyer - Cancer Research Center of Lyon
Olga M. Sinilnikova - Cancer Research Center of Lyon
Ontario Canc Genetics Network
Publication Details: Human molecular genetics, Vol.20(23), pp.4732-4747
Publisher: Oxford Univ Press
Number of pages: 16
Date published: 01/12/2011
Grant note: Fundacion Mutua Madrilena; Instituto de Salud Carlos III U01 CA69417 / Northern California Cancer Center 132473 / Academy of Finland; Research Council of Finland Komen Foundation for the Cure; Susan G. Komen Breast Cancer Foundation GOG's Cancer Prevention and Control Committee 223175 (HEALTH-F2-2009-223175) / European Community; European Commission P30-CA051008 / Tissue Culture Shared Registry at Georgetown University (NIH/NCI); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) G0801875 / MRC; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) CRUK; Cancer Research UK LIGUE CONTRE LE CANCER; Ligue nationale contre le cancer 91109024 / ZonMW; Netherlands Organization for Health Research and Development National Breast Cancer Foundation Sigrid Juselius Foundation Association 'Le cancer du sein, parlons-en!' 11022; 11174; 10118 / Cancer Research UK FIS PI08 1120 / Spanish Ministry of Science and Innovation; Spanish Government Royal Marsden NHS Foundation Trust; Royal Society of New Zealand; Marsden Fund (NZ) U01 CA69398 / Columbia University CA128978 / US National Cancer Institute, National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Cancer Foundation of Western Australia; Cancer Council Western Australia DKFZ; Helmholtz Association Helsinki University G0801875 / Medical Research Council; UK Research & Innovation (UKRI); Medical Research Council UK (MRC) Alleanza Contro il Cancro Ministero della Salute (P.I.O. V and 'Progetto Tumori Femminili'); Ministry of Health, Italy Cancer Care Ontario U01 CA69467 / Cancer Care Ontario 019511 / Canadian Breast Cancer Research Alliance Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Council New South Wales HHSN261200744000C / Cancer Genetics Network U01 CA69631 / Fox Chase Cancer Center Breast Cancer Research Foundation BCFR OSU Comprehensive Cancer Center W81XWH-10-1-0341 / Department of Defense; United States Department of Defense RFA-CA-06-503 / National Cancer Institute, National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 145684; 288704; 454508 / National Health and Medical Research Council (NHMRC); National Health and Medical Research Council (NHMRC) of Australia US National Cancer Institute; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) C1287/A10118; C1287/A11990; C5047/A8385 / Cancer Research UK Ministero dell'Universitae della Ricerca (MIUR); Ministry of Education, Universities and Research (MIUR) INSERM/INCa; Institut National de la Sante et de la Recherche Medicale (Inserm); Institut National du Cancer (INCA) France U01 CA69638 / University of Melbourne 107054 / German Cancer Aid; Deutsche Krebshilfe Finnish Cancer Society Breast Cancer Research Foundation (BCRF) Canadian Institutes of Health Research; Canadian Institutes of Health Research (CIHR) Queensland Cancer Fund AICR-07-0454 / Association for International Cancer Research NKI1998-1854; NKI2004-3088; NKI2007-3756 / Dutch Cancer Society; KWF Kankerbestrijding N02PC45022-46 / Georgetown University Informatics Support Center (RFP) Susan G. Komen Foundation; Susan G. Komen Breast Cancer Foundation Ligue National Contre le Cancer; Ligue nationale contre le cancer Eileen Stein Jacoby Fund NF-SI-0510-10096 / National Institute for Health Research; National Institutes of Health Research (NIHR) NO2-CP-11019-50; N02-CP-65504 / Westat, Inc., Rockville, MD NIHR; National Institutes of Health Research (NIHR) NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) NEYE U01 CA69446 / Huntsman Cancer Institute Familial Cancer Registry Asociacion Espanola Contra el Cancer Swing Fore the Cure RD06/0020/0021 / Instituto de Salud Carlos III; Spanish Government
Identifiers: 99822263502346
Academic Unit: School of Health Sciences
Language: English
Resource Type: Journal article

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers

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