Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Mia M. Gaudet; Chris Jacobs; Karoline B. Kuchenbaecker; Joseph Vijai; Robert J. Klein; Tomas Kirchhoff; Lesley McGuffog; Daniel Barrowdale; Alison M. Dunning; Andrew Lee; Joe Dennis; Sue Healey; Ed Dicks; Penny Soucy; Olgam Sinilnikova; Vernon S. Pankratz; Xianshu Wang; Ronald C. Eldridge; Daniel C. Tessier; Daniel Vincent; Francois Bacot; Frans B. L. Hogervorst; Susan Peock; Dominique Stoppa-Lyonnet; Paolo Peterlongo; Rita K. Schmutzler; Katherine L. Nathanson; Marion Piedmonte; Christian F. Singer; Mads Thomassen; Thomas V. O. Hansen; Susan L. Neuhausen; Ignacio Blanco; Mark H. Greene; Judith Garber; Jeffrey N. Weitzel; Irene L. Andrulis; David E. Goldgar; Emma D'Andrea; Trinidad Caldes; Heli Nevanlinna; Ana Osorio; Elizabeth J. van Rensburg; Adalgeir Arason; Gad Rennert; Ans M. W. van den Ouweland; Annemarie H. van der Hout; Carolien M. Kets; Cora M. Aalfs; Juul T. Wijnen; Margreet G. E. M. Ausems; Debra Frost; Steve Ellis; Elena Fineberg; Radka Platte; D. Gareth Evans; Julian Adlard; Marc Tischkowitz; Mary E. Porteous; Francesca Damiola; Lisa Golmard; Laure Barjhoux; Michel Longy; Muriel Belotti; Sandra Fert Ferrer; Sylvie Mazoyer; Amanda B. Spurdle; Siranoush Manoukian; Monica Barile; Maurizio Genuardi; Norbert Arnold; Alfons Meindl; Christian Sutter; Barbara Wappenschmidt; Susan M. Domchek; Georg Pfeiler; Eitan Friedman; Uffe Birk Jensen; Mark Robson; Sohela Shah; Conxi Lazaro; Phuong L. Mai; Javier Benitez; Melissa C. Southey; Marjanka K. Schmidt; Peter A. Fasching; Julian Peto; Manjeet K. Humphreys; Qin Wang; Kyriaki Michailidou; Elinor J. Sawyer; Barbara Burwinkel; Pascal Guenel; Stig E. Bojesen; Roger L. Milne; Hermann Brenner; Magdalena Lochmann; Kristiina Aittomaki; Thilo Doerk; Sara Margolin; Arto Mannermaa; Diether Lambrechts; Jenny Chang-Claude; Paolo Radice; Graham G. Giles; Christopher A. Haiman; Robert Winqvist; Peter Devillee; Montserrat Garcia-Closas; Nils Schoof; Maartje J. Hooning; Angela Cox; Paul D. P. Pharoah; Anna Jakubowska; Nick Orr; Anna Gonzalez-Neira; Guillermo Pita; M. Rosario Alonso; Per Hall; Fergus J. Couch; Jacques Simard; David Altshuler; Douglas F. Easton; Georgia Chenevix-Trench; Antonis C. Antoniou; Kenneth Offit; KConFab Investigators

doi:10.1371/journal.pgen.1003173

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Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Journal article

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Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

Mia M. Gaudet, Chris Jacobs, Karoline B. Kuchenbaecker, Joseph Vijai, Robert J. Klein, Tomas Kirchhoff, Lesley McGuffog, Daniel Barrowdale, Alison M. Dunning, Andrew Lee, …

PLoS genetics, Vol.9(3), pp.e1003173-e1003173

01/03/2013

DOI: https://doi.org/10.1371/journal.pgen.1003173

PMID: 23544012

Abstract

Genetics & Heredity

Life Sciences & Biomedicine

Science & Technology

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 x 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

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Title: Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk
Creators: Mia M. Gaudet - Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA
Chris Jacobs - Guys & St Thomas NHS Fdn Trust, London, England
Karoline B. Kuchenbaecker - University of Cambridge
Joseph Vijai - Mécanique et Engrenage Moderne
Robert J. Klein - Mécanique et Engrenage Moderne
Tomas Kirchhoff - Supreme Council Of Health
Lesley McGuffog - University of Cambridge
Daniel Barrowdale - University of Cambridge
Alison M. Dunning - University of Cambridge
Andrew Lee - University of Cambridge
Joe Dennis - University of Cambridge
Sue Healey - College Station Medical Center
Ed Dicks - University of Cambridge
Penny Soucy - Université du Québec
Olgam Sinilnikova - Hosp Civils Lyon, Unite Mixte Genet Constitut Canc Frequents, Ctr Leon Berard, Lyon, France
Vernon S. Pankratz - Inserm
Xianshu Wang - Mayo Clin, Dept Hlth Sci, Rochester, MN USA
Ronald C. Eldridge - College Station Medical Center
Daniel C. Tessier - Emory University
Daniel Vincent - Ctr Innovat Genome Quebec, Montreal, PQ, Canada
Francois Bacot - Ctr Innovat Genome Quebec, Montreal, PQ, Canada
Frans B. L. Hogervorst - Netherlands Canc Inst, Family Canc Clin, Amsterdam, Netherlands
Susan Peock - University of Cambridge
Dominique Stoppa-Lyonnet - Institute Curie
Paolo Peterlongo - Predict
Rita K. Schmutzler - Univ Hosp Cologne, Cologne, Germany
Katherine L. Nathanson - Supreme Council Of Health
Marion Piedmonte - Roswell Pk Canc Inst, Gynecol Oncol Grp, Stat & Data Ctr, Buffalo, NY 14263 USA
Christian F. Singer - University of Vienna
Mads Thomassen - Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense, Denmark
Thomas V. O. Hansen - College Station Medical Center
Susan L. Neuhausen - City of Hope
Ignacio Blanco - IDIBELL Catalan Inst Oncol, Genet Counseling Unit, Hereditary Canc Program, Barcelona, Spain
Mark H. Greene - NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA
Judith Garber - CancerCare
Jeffrey N. Weitzel - City Hope Natl Med Ctr, Clin Canc Genet, City Hope Clin Canc Genet Community Res Network, Duarte, CA USA
Irene L. Andrulis - Lunenfeld-Tanenbaum Research Institute
David E. Goldgar - University of Utah
Emma D'Andrea - Univ Padua, Dept Surg Oncol & Gastroenterol, Padua, Italy
Trinidad Caldes - Instituto de Investigación Sanitaria del Hospital Clínico San Carlos
Heli Nevanlinna - University of Helsinki
Ana Osorio - Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain
Elizabeth J. van Rensburg - University of Pretoria
Adalgeir Arason - National University Hospital of Iceland
Gad Rennert - Clalit Natl Israeli Canc Control Ctr, Haifa, Israel
Ans M. W. van den Ouweland - College Station Medical Center
Annemarie H. van der Hout - University of Groningen
Carolien M. Kets - Radboud University Nijmegen
Cora M. Aalfs - University of Amsterdam
Juul T. Wijnen - Leiden University
Margreet G. E. M. Ausems - College Station Medical Center
Debra Frost - University of Cambridge
Steve Ellis - University of Cambridge
Elena Fineberg - University of Cambridge
Radka Platte - University of Cambridge
D. Gareth Evans - University of Cambridge
Julian Adlard - Yorkshire Reg Genet Serv, Leeds, W Yorkshire, England
Marc Tischkowitz - University of Cambridge
Mary E. Porteous - Western Gen Hosp, South East Scotland Reg Genet Serv, Edinburgh EH4 2XU, Midlothian, Scotland
Francesca Damiola - Inserm
Lisa Golmard - Institute Curie
Laure Barjhoux - Inserm
Michel Longy - University of Bordeaux
Muriel Belotti - Institute Curie
Sandra Fert Ferrer - Hotel Dieu Ctr Hosp, Lab Genet Chromosom, Chambery, France
Sylvie Mazoyer - Inserm
Amanda B. Spurdle - College Station Medical Center
Siranoush Manoukian - Predict
Monica Barile - Mylan
Maurizio Genuardi - University of Florence
Norbert Arnold - Kiel University
Alfons Meindl - Ludwig Maximilian University of Munich
Christian Sutter - Heidelberg University
Barbara Wappenschmidt - Univ Hosp Cologne, Cologne, Germany
Susan M. Domchek - Supreme Council Of Health
Georg Pfeiler - University of Vienna
Eitan Friedman - College Station Medical Center
Uffe Birk Jensen - Aarhus University
Mark Robson - Mécanique et Engrenage Moderne
Sohela Shah - Mécanique et Engrenage Moderne
Conxi Lazaro - IDIBELL Catalan Inst Oncol, Hereditary Canc Program, Mol Diagnost Unit, Barcelona, Spain
Phuong L. Mai - NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA
Javier Benitez - Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain
Melissa C. Southey - University of Melbourne
Marjanka K. Schmidt - Antoni van Leeuwenhoek Hosp, Netherlands Canc Inst, Amsterdam, Netherlands
Peter A. Fasching - Univ Hosp Erlangen, Univ Breast Ctr Franconia, Dept Gynecol & Obstet, Erlangen, Germany
Julian Peto - Supreme Council Of Health
Manjeet K. Humphreys - University of Cambridge
Qin Wang - University of Cambridge
Kyriaki Michailidou - University of Cambridge
Elinor J. Sawyer - NIHR
Barbara Burwinkel - Heidelberg Univ, Dept Obstet & Gynecol, Heidelberg, Germany
Pascal Guenel - Inserm
Stig E. Bojesen - Copenhagen Gen Populat Study, Copenhagen, Denmark
Roger L. Milne - Spanish Natl Canc Ctr CNIO, Human Genet Grp, Madrid, Spain
Hermann Brenner - Heidelberg
Magdalena Lochmann - Ludwig Maximilian University of Munich
Kristiina Aittomaki - University of Helsinki
Thilo Doerk - Supreme Council Of Health
Sara Margolin - Karolinska Institutet
Arto Mannermaa - University of Eastern Finland
Diether Lambrechts - KU Leuven
Jenny Chang-Claude - Heidelberg
Paolo Radice - Predict
Graham G. Giles - Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia
Christopher A. Haiman - Supreme Council Of Health
Robert Winqvist - University of Oulu
Peter Devillee - Leiden University
Montserrat Garcia-Closas - Inst Canc Res, Div Genet & Epidemiol, Sutton, Surrey, England
Nils Schoof - Karolinska Institutet
Maartje J. Hooning - College Station Medical Center
Angela Cox - University of Sheffield
Paul D. P. Pharoah - University of Cambridge
Anna Jakubowska - College Station Medical Center
Nick Orr - Breakthrough
Anna Gonzalez-Neira - Spanish Natl Canc Res Ctr CNIO, Human Genotyping CEGEN Unit, Human Canc Genet Program, Madrid, Spain
Guillermo Pita - Spanish Natl Canc Res Ctr CNIO, Human Genotyping CEGEN Unit, Human Canc Genet Program, Madrid, Spain
M. Rosario Alonso - Spanish Natl Canc Res Ctr CNIO, Human Genotyping CEGEN Unit, Human Canc Genet Program, Madrid, Spain
Per Hall - Breakthrough
Fergus J. Couch - Mayo Clin, Dept Hlth Sci, Rochester, MN USA
Jacques Simard - Université du Québec
David Altshuler - College Station Medical Center
Douglas F. Easton - University of Cambridge
Georgia Chenevix-Trench - College Station Medical Center
Antonis C. Antoniou - University of Cambridge
Kenneth Offit - Mécanique et Engrenage Moderne
KConFab Investigators
Publication Details: PLoS genetics, Vol.9(3), pp.e1003173-e1003173
Publisher: Public Library Science
Number of pages: 15
Date published: 01/03/2013
Grant note: Fondazione Italiana per la Ricerca sul Cancro; Fondazione AIRC per la ricerca sul cancro U.S. National Cancer Institute (NIH/NCI) Italian citizens Niehaus Clinical Cancer Genetics Initiative Komen Foundation for the Cure; Susan G. Komen Breast Cancer Foundation Breakthrough Breast Cancer Victorian Cancer Agency RUL 1997-1505; DDHK 2004-3124; DDHK 2009-4318 / Dutch Cancer Society; KWF Kankerbestrijding 11-04-00227; 12-04-00928; 12-04-01490 / Russian Federation for Basic Research; Russian Foundation for Basic Research (RFBR) Israel Cancer Association IG 8713 / Italian Association for Cancer Research (AIRC); Fondazione AIRC per la ricerca sul cancro 209057; 251553; 504711 / Australian NHMRC; National Health and Medical Research Council (NHMRC) of Australia Cancer Research Initiatives Foundation Academy of Finland; Research Council of Finland Rooney Family Foundation CRUK; Cancer Research UK Helen Diller Family Comprehensive Cancer Center; University of California System 03/DHCS/03/G121/51 / National Institute for Health Research; National Institutes of Health Research (NIHR) National Breast Cancer Foundation Ralph and Marion Falk Medical Research Trust Institute of Cancer Research (ICR) UCSF Cancer Risk Program 199600 / NHMRC; National Health and Medical Research Council (NHMRC) of Australia U.S. National Institute of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 10124 / Cancer Research UK; The Francis Crick Institute; Cancer Research UK NO2-CP-11019-50; N02-CP-65504 / Westat, Rockville, MD Cancer Councils of New South Wales, South Australia; Cancer Council New South Wales Italian Ministry of Health ("Progetto Tumori Femminili") 110135 / Cancer Foundation Finland sr Intramural Research Program of the US National Cancer Institute, NIH SIOP-06-258-01-COUN / American Cancer Society Cancer Foundation of Western Australia; Cancer Council Western Australia Jewish General Hospital UM.C/HlR/MOHE/06 / Ministry of Science, Technology and Innovation, Ministry of Higher Education IF-12-06 / National Breast Cancer Foundation S295; S299; S305PA / Yorkshire Cancer Research W81XWH-10-1-0341 / U.S. Department of Defence Ovarian Cancer Idea award CRN-87521 / Canadian Institutes of Health Research; Canadian Institutes of Health Research (CIHR) 02.740.11.0780 / Federal Agency for Science and Innovations, Russia; Federal Agency for Science & Innovations (FASI) Ohio State University Comprehensive Cancer Center UM.C/HIR/MOHE/06 / Ministry of Higher Education; Science and Technology Development Fund (STDF); Ministry of Higher Education & Scientific Research (MHESR) Association "Le cancer du sein, parlons-en!" Award Oulu University Hospital CA116201 / NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Breast Cancer Research Foundation BBMRI-NL CP16 / Biobanking and Biomolecular Resources Research Infrastructure Susan G. Komen Foundation for the Cure; Susan G. Komen Breast Cancer Foundation NHMRC; National Health and Medical Research Council (NHMRC) of Australia KULPFV/10/016-SymBioSysII Agency for Science, Technology and Research of Singapore (A*STAR); Agency for Science Technology & Research (A*STAR) Cancer Council of Tasmania; Cancer Council Tasmania Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program; Canadian Institutes of Health Research (CIHR) Quebec Breast Cancer Foundation University of Oulu University of Eastern Finland Lymphoma Foundation Cancer Australia 628333 / Cancer Australia NHS VicHealth and Cancer Council Victoria; Canadian Institutes of Health Research (CIHR); Cancer Council Victoria Finnish Cancer Foundation Malaysian Ministry of Science, Technology and Innovation; Ministry of Energy, Science, Technology, Environment and Climate Change (MESTECC), Malaysia R01-CA102776; R01-CA083855 / National Institutes of Health (NIH); United States Department of Health & Human Services; National Institutes of Health (NIH) - USA German Cancer Research Center CA128978; CA63464; CA54281; CA098758; CA132839 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA PSR-SIIRI-701 / Ministry of Economic Development, Innovation and Export Trade Cancer Councils of New South Wales, Victoria; Cancer Council New South Wales Hamburg Cancer Society Breast Cancer Research Foundation (BCRF) Queensland Cancer Fund Marit and Hans Rausings Initiative Against Breast Cancer 232-2008; 196-2010 / Stichting tegen Kanker DAMD17-01-1-0729 / United States Army Medical Research and Materiel Command; United States Department of Defense; United States Army; U.S. Army Medical Research & Materiel Command (USAMRMC) 70-2892-BR I / Deutsche Krebshilfe e.V.; Deutsche Krebshilfe Facdonald Family Foundation Ligue National Contre le Cancer; Ligue nationale contre le cancer Cancer Fund of North Savo FWO National Cancer Institute, Department of Health and Human Services, USA; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 16565; 10118; 11022; 16561; 11174 / Cancer Research UK Swedish Cancer Society Entertainment Industry Fund National Women's Cancer Research Alliance, Clalit Health Services in Israel Andrew Sabin Family Foundation Jonsson Comprehensive Cancer Center Foundation Susan G. Komen Breast Cancer Foundation 01KH0402 / Federal Ministry of Education and Research (BMBF); Federal Ministry of Education & Research (BMBF) 1020350 / National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea; Ministry of Health & Welfare (MOHW), Republic of Korea Cancer Councils of New South Wales, Tasmania; Cancer Council New South Wales Fondazione IRCCS Istituto Nazionale Tumori [C490/A10124][C8197/A10123 / Cancer Research UK National Health and Medical Research Council (NHMRC); National Health and Medical Research Council (NHMRC) of Australia
Identifiers: 99822359002346
Academic Unit: School of Health Sciences
Language: English
Resource Type: Journal article

Identification of a BRCA2-Specific Modifier Locus at 6p24 Related to Breast Cancer Risk

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