Abstract
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 5 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 4732-4747 |
| Number of pages | 16 |
| Journal | Human molecular genetics |
| Volume | 20 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 1 2011 |
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
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In: Human molecular genetics, Vol. 20, No. 23, 01.12.2011, p. 4732-4747.
Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers
AU - Cox, David G.
AU - Simard, Jacques
AU - Sinnett, Daniel
AU - Hamdi, Yosr
AU - Soucy, Penny
AU - Ouimet, Manon
AU - Barjhoux, Laure
AU - Verny-Pierre, Carole
AU - McGuffog, Lesley
AU - Healey, Sue
AU - Szabo, Csilla
AU - Greene, Mark H.
AU - Mai, Phuong L.
AU - Andrulis, Irene L.
AU - Glendon, Gord
AU - Selander, Teresa
AU - Weerasooriya, Nayana
AU - Thomassen, Mads
AU - Gerdes, Anne Marie
AU - Caligo, Maria A.
AU - Friedman, Eitan
AU - Laitman, Yael
AU - Kaufman, Bella
AU - Paluch, Shani S.
AU - Borg, Åke
AU - Karlsson, Per
AU - Askmalm, Marie Stenmark
AU - Bustinza, Gisela Barbany
AU - Nathanson, Katherine L.
AU - Domchek, Susan M.
AU - Rebbeck, Timothy R.
AU - Benítez, Javier
AU - Hamann, Ute
AU - Rookus, Matti A.
AU - van den Ouweland, Ans M.W.
AU - Ausems, Margreet G.E.M.
AU - Aalfs, Cora M.
AU - van Asperen, Christi J.
AU - Devilee, Peter
AU - Gille, Hans J.J.P.
AU - Peock, Susan
AU - Frost, Debra
AU - Evans, D. Gareth
AU - Eeles, Ros
AU - Izatt, Louise
AU - Adlard, Loeter Devilee
AU - Paterson, Joan
AU - Eason, Jacqueline
AU - Godwin, Andrew K.
AU - Remon, Marie Alice
AU - Moncoutier, Virginie
AU - Gauthier-Villars, Marion
AU - Lasset, Christine
AU - Giraud, Sophie
AU - Hardouin, Agnès
AU - Berthet, Pascaline
AU - Sobol, Hagay
AU - Eisinger, François
AU - de Paillerets, Brigitte Bressac
AU - Caron, Olivier
AU - Delnatte, Capucine
AU - Goldgar, David
AU - Miron, Alex
AU - Ozcelik, Hilmi
AU - Buys, Saundra
AU - Southey, Melissa C.
AU - Terry, Mary Beth
AU - Singer, Christian F.
AU - Dressler, Anne Catharina
AU - Tea, Muy Kheng
AU - Hansen, Thomas V.O.
AU - Johannsson, Oskar
AU - Piedmonte, Marion
AU - Rodriguez, Gustavo C.
AU - Basil, Jack B.
AU - Blank, Stephanie
AU - Toland, Amanda E.
AU - Montagna, Marco
AU - Isaacs, Claudine
AU - Blanco, Ignacio
AU - Gayther, Simon A.
AU - Moysich, Kirsten B.
AU - Schmutzler, Rita K.
AU - Wappenschmidt, Barbara
AU - Engel, Christoph
AU - Meindl, Alfons
AU - Ditsch, Nina
AU - Arnold, Norbert
AU - Niederacher, Dieter
AU - Sutter, Christian
AU - Gadzicki, Dorothea
AU - Fiebig, Britta
AU - Caldes, Trinidad
AU - Laframboise, Rachel
AU - Nevanlinna, Heli
AU - Chen, Xiaoqing
AU - Beesley, Jonathan
AU - Spurdle, Amanda B.
AU - Neuhausen, Susan L.
AU - Ding, Yuan C.
AU - Couch, Fergus J.
AU - Wang, Xianshu
AU - Peterlongo, Paolo
AU - Manoukian, Siranoush
AU - Bernard, Loris
AU - Radice, Paolo
AU - Easton, Douglas F.
AU - Chenevix-Trench, Georgia
AU - Antoniou, Antonis C.
AU - Stoppa-Lyonnet, Dominique
AU - Mazoyer, Sylvie
AU - Sinilnikova, Olga M.
AU - Nordling, Margareta
AU - Bergman, Annika
AU - Einbeigi, Zakaria
AU - Stenmark-Askmalm, Marie
AU - Liedgren, Sigrun
AU - Borg, Åke
AU - Loman, Niklas
AU - Olsson, Håkan
AU - Kristoffersson, Ulf
AU - Soller, Maria
AU - Jernström, Helena
AU - Harbst, Katja
AU - Henriksson, Karin
AU - Lindblom, Annika
AU - Arver, Brita
AU - von Wachenfeldt, Anna
AU - Liljegren, Annelie
AU - Barbany-Bustinza, Gisela
AU - Rantala, Johanna
AU - Melin, Beatrice
AU - Grönberg, Henrik
AU - Stattin, Eva Lena
AU - Emanuelsson, Monica
AU - Ehrencrona, Hans
AU - Brandell, Richard Rosenquist
AU - Dahl, Niklas
AU - Hogervorst, F. B.L.
AU - Verhoef, S.
AU - Verheus, M.
AU - van't Veer, L. J.
AU - van Leeuwen, F. E.
AU - Rookus, M. A.
AU - Collée, M.
AU - Jager, A.
AU - Hooning, M. J.
AU - Tilanus-Linthorst, M. M.A.
AU - Seynaeve, C.
AU - van Asperen, C. J.
AU - Wijnen, J. T.
AU - Vreeswijk, M. P.
AU - Tollenaar, R. A.
AU - Ligtenberg, M. J.
AU - Hoogerbrugge, N.
AU - Ausems, M. G.
AU - van der Luijt, R. B.
AU - Aalfs, C. M.
AU - van Os, T. A.
AU - Gille, J. J.P.
AU - Waisfisz, Q.
AU - Meijers-Heijboer, H. E.J.
AU - Gomez-Garcia, E. B.
AU - van Roozendaal, C. E.
AU - Blok, Marinus J.
AU - Caanen, B.
AU - Oosterwijk, J. C.
AU - van der Hout, A. H.
AU - Mourits, M. J.
AU - Vasen, H. F.
AU - Peock, Susan
AU - Cook, Margaret
AU - Frost, Debra
AU - Platte, Radka
AU - Miedzybrodzka, Zosia
AU - Gregory, Helen
AU - Morrison, Patrick
AU - Jeffers, Lisa
AU - Cole, Trevor
AU - Ong, Kai Ren
AU - Hoffman, Jonathan
AU - Donaldson, Alan
AU - James, Margaret
AU - Paterson, Joan
AU - Downing, Sarah
AU - Taylor, Amy
AU - Murray, Alexandra
AU - Rogers, Mark T.
AU - McCann, Emma
AU - Kennedy, M. John
AU - Barton, David
AU - Porteous, Mary
AU - Drummond, Sarah
AU - Brewer, Carole
AU - Kivuva, Emma
AU - Searle, Anne
AU - Goodman, Selina
AU - Hill, Kathryn
AU - Davidson, Rosemarie
AU - Murday, Victoria
AU - Bradshaw, Nicola
AU - Snadden, Lesley
AU - Longmuir, Mark
AU - Watt, Catherine
AU - Gibson, Sarah
AU - Haque, Eshika
AU - Tobias, Ed
AU - Duncan, Alexis
AU - Izatt, Louise
AU - Jacobs, Chris
AU - Langman, Caroline
AU - Whaite, Anna
AU - Dorkins, Huw
AU - Barwell, Julian
AU - Adlard, Julian
AU - Chu, Carol
AU - Miller, Julie
AU - Ellis, Ian
AU - Houghton, Catherine
AU - Lalloo, Fiona
AU - Taylor, Jane
AU - Side, Lucy
AU - Male, Alison
AU - Berlin, Cheryl
AU - Eason, Jacqueline
AU - Collier, Rebecca
AU - Douglas, Fiona
AU - Claber, Oonagh
AU - Jobson, Irene
AU - Walker, Lisa
AU - McLeod, Diane
AU - Halliday, Dorothy
AU - Durell, Sarah
AU - Stayner, Barbara
AU - Eeles, Ros
AU - Shanley, Susan
AU - Rahman, Nazneen
AU - Houlston, Richard
AU - Bancroft, Elizabeth
AU - D'Mello, Lucia
AU - Page, Elizabeth
AU - Ardern-Jones, Audrey
AU - Kohut, Kelly
AU - Wiggins, Jennifer
AU - Castro, Elena
AU - Mitra, Anita
AU - Robertson, Lisa
AU - Cook, Jackie
AU - Quarrell, Oliver
AU - Bardsley, Cathryn
AU - Hodgson, Shirley
AU - Goff, Sheila
AU - Brice, Glen
AU - Winchester, Lizzie
AU - Eddy, Charlotte
AU - Tripathi, Vishakha
AU - Attard, Virginia
AU - Eccles, Diana
AU - Lucassen, Anneke
AU - Crawford, Gillian
AU - McBride, Donna
AU - Smalley, Sarah
AU - Sinilnikova, Olga
AU - Barjhoux, Laure
AU - Verny-Pierre, Carole
AU - Giraud, Sophie
AU - Léone, Mélanie
AU - Mazoyer, Sylvie
AU - Stoppa-Lyonnet, Dominique
AU - Gauthier-Villars, Marion
AU - Buecher, Bruno
AU - Houdayer, Claude
AU - Moncoutier, Virginie
AU - Belotti, Muriel
AU - Tirapo, Carole
AU - de Pauw, Antoine
AU - Bressac-de-Paillerets, Brigitte
AU - Remenieras, Audrey
AU - Byrde, Véronique
AU - Caron, Olivier
AU - Lenoir, Gilbert
AU - Bignon, Yves Jean
AU - Uhrhammer, Nancy
AU - Bonadona, Valérie
AU - Hardouin, Agnès
AU - Berthet, Pascaline
AU - Sobol, Hagay
AU - Bourdon, Violaine
AU - Noguchi, Tetsuro
AU - Eisinger, François
AU - Coulet, Florence
AU - Colas, Chrystelle
AU - Soubrier, Florent
AU - Coupier, Isabelle
AU - Pujol, Pascal
AU - Peyrat, Jean Philippe
AU - Fournier, Joëlle
AU - Révillion, Françoise
AU - Vennin, Philippe
AU - Adenis, Claude
AU - Rouleau, Etienne
AU - Lidereau, Rosette
AU - Demange, Liliane
AU - Nogues, Catherine
AU - Muller, Danièle
AU - Fricker, Jean Pierre
AU - Longy, Michel
AU - Sevenet, Nicolas
AU - Toulas, Christine
AU - Guimbaud, Rosine
AU - Gladieff, Laurence
AU - Feillel, Viviane
AU - Leroux, Dominique
AU - Dreyfus, Hélène
AU - Rebischung, Christine
AU - Coron, Fanny
AU - Faivre, Laurence
AU - Prieur, Fabienne
AU - Lebrun, Marine
AU - Ferrer, Sandra Fert
AU - Frénay, Marc
AU - Vénat-Bouvet, Laurence
N1 - Funding Information: The Breast Cancer Family Registry (BCFR): BCFR is supported by the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the BCFR and Principal Investigators, including Cancer Care Ontario (U01 CA69467), Columbia University (U01 CA69398), Fox Chase Cancer Center (U01 CA69631), Huntsman Cancer Institute (U01 CA69446), Northern California Cancer Center (U01 CA69417), University of Melbourne (U01 CA69638) and the Georgetown University Informatics Support Center (RFP No. N02PC45022-46). Samples from the NCCC, FCCC and HCI were processed and distributed by the Coriell Institute for Medical Research. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR. Funding Information: Ontario Cancer Genetics Network (OCGN): We wish to thank Gord Glendon, Teresa Selander, Nayana Weerasooriya and members of the Ontario Cancer Genetics Network for their contributions to the study. The OCGN is supported by Cancer Care Ontario. Funding Information: We thank Leigha Senter and Kevin Sweet for accrual of study participants and Michelle O’Connor and Caroline Craven for database entry. The OSU Human Genetics Sample Bank processed DNA samples and the OSU CCC Nucleic Acids Shared Resource performed the Taqman Plate Reads. This work was supported by funds from the OSU Comprehensive Cancer Center. Funding Information: Copenhagen Breast Cancer Study (CBCS): We would like to thank Bent Ejlertsen, Mette K. Andersen, and Susanne Kjaergaard for clinical data. Moreover, we thank the NEYE Foundation for financial support. Funding Information: Hospital Clinico San Carlos (HCSC): The HCSC study was partially supported by Instituto de Salud Carlos III: RD06/ 0020/0021. We wish to thank Dr Miguel de la Hoya and Pedro Perez-Segura for their contribution to this study. Funding Information: Mayo Clinic (MAYO): This work was supported by grants from the Breast Cancer Research Foundation (BCRF), Komen Foundation for the Cure, Department of Defense ovarian cancer research award (W81XWH-10-1-0341) and US National Cancer Institute, National Institutes of Health grant CA128978. Funding Information: Istituto Oncologico Veneto – Hereditary Breast Ovarian Cancer Study (IOVHBOCS): The study was supported by the Ministero dell’Università e della Ricerca (MIUR), Ministero della Salute (P.I.O. V and ‘Progetto Tumori Femminili’) and Alleanza Contro il Cancro. Funding Information: The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON): HEBON Collaborating Centers: Coordinating center: Netherlands Cancer Institute, Amsterdam, NL: F.B.L. Hogervorst, S. Verhoef, M. Verheus, L.J. van’t Veer, F.E. van Leeuwen, M.A. Rookus; Erasmus Medical Center, Rotterdam, NL: M. Collée, A.M.W. van den Ouweland, A. Jager, M.J. Hooning, M.M.A. Tilanus-Linthorst, C. Seynaeve; Leiden University Medical Center, NL, Leiden: C.J. van Asperen, J.T. Wijnen, M.P. Vreeswijk, R.A. Tollenaar, P. Devilee; Radboud University Nijmegen Medical Center, Nijmegen, NL: M.J. Ligtenberg, N. Hoogerbrugge; University Medical Center Utrecht, Utrecht, NL: M.G. Ausems, R.B. van der Luijt; Amsterdam Medical Center, NL: C.M. Aalfs, T.A. van Os; VU University Medical Center, Amsterdam, NL: J.J.P. Gille, Q. Waisfisz, H.E.J. Meijers-Heijboer; University Hospital Maastricht, Maastricht, NL: E.B. Gomez-Garcia, C.E. van Roozendaal, Marinus J. Blok, B. Caanen; University Medical Center Groningen University, NL: J.C. Oosterwijk, A.H. van der Hout, M.J. Mourits; The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden, NL: H.F. Vasen. The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756 and the ZonMW grant 91109024. Funding Information: University of California Irvine (UCI) (now the Beckman Research Institute of City of Hope): Genotyping at UCI was funded by grant NIH CA74415. Funding Information: UK and Gilda Radner Familial Ovarian Cancer Registries (UKGRFOCR): UKFOCR was supported by a project grant from CRUK to Paul Pharoah. We thank Paul Pharoah, Susan Ramus, Carole Pye, Patricia Harrington and Eva Wozniak for their contributions towards the UKFOCR. We’d like to acknowledge the Roswell Park Alliance Foundation for their continued support of the Gilda Radner Ovarian Family Cancer Registry. GRFOCR would like to acknowledge Lara Sucheston (Department of Cancer Prevention and Control) and Kunle Odunsi (Departments Gynecologic Oncology and Immunology). Funding Information: Georgetown University (GEORGETOWN): C.I. received support from the Familial Cancer Registry and the Tissue Culture Shared Registry at Georgetown University (NIH/ NCI grant P30-CA051008), the Cancer Genetics Network (HHSN261200744000C), and Swing Fore the Cure. Funding Information: Fox Chase Cancer Centre (FCCC): University of Kansas Medical Center (KUMC): A.K.G. was funded by R01CA140323, U01CA69631, 5U01CA113916, and the Eileen Stein Jacoby Fund. Funding Information: Deutsches Krebsforschungszentrum (DKFZ): The DKFZ study was supported by the DKFZ. We thank Diana Torres and Muhammad U. Rashid for providing DNA samples and supplying data. We thank Antje Seidel-Renkert for expert technical assistance. Funding Information: Spanish National Cancer Centre (CNIO): This study was partially supported by Fundación Mutua Madrileña, Asocia-ción Española Contra el Cáncer and the Spanish Ministry of Science and Innovation (FIS PI08 1120). Funding Information: Epidemiological study of BRCA1 & BRCA2 mutation carriers (EMBRACE): Douglas F. Easton is the PI of the study. EMBRACE Collaborating Centers are: Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, Debra Frost, Radka Platte. North of Scotland Regional Genetics Service, Aberdeen: Zosia Miedzybrodzka, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison, Lisa Jeffers. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Kai-ren Ong, Jonathan Hoffman. South West Regional Genetics Service, Bristol: Alan Donaldson, Margaret James. East Anglian Regional Genetics Service, Cambridge: Joan Paterson, Sarah Downing, Amy Taylor. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, Mark T. Rogers, Emma McCann. St James’s Hospital, Dublin & National Centre for Medical Genetics, Dublin: M. John Kennedy, David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Sarah Drummond. Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman, Kathryn Hill. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt, Sarah Gibson, Eshika Haque, Ed Tobias, Alexis Duncan. South East Thames Regional Genetics Service, Guy’s Hospital London: Louise Izatt, Chris Jacobs, Caroline Langman, Anna Whaite. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Julian Adlard, Carol Chu, Julie Miller. Merseyside & Cheshire Clinical Genetics Service, Liverpool: Ian Ellis, Catherine Houghton. Manchester Regional Genetics Service, Manchester: D Gareth Evans, Fiona Lalloo, Jane Taylor. North East Thames Regional Genetics Service, NE Thames, London: Lucy Side, Alison Male, Cheryl Berlin. Nottingham Centre for Medical Genetics, Nottingham: Jacqueline Eason, Rebecca Collier. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber, Irene Jobson. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod, Dorothy Hal-liday, Sarah Durell, Barbara Stayner. The Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Ros Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Lucia D’Mello, Elizabeth Page, Audrey Ardern-Jones, Kelly Kohut, Jennifer Wiggins, Elena Castro, Anita Mitra, Lisa Robertson. North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell, Cathryn Bardsley. South West Thames Regional Genetics Service, London: Shirley Hodgson, Sheila Goff, Glen Brice, Lizzie Winchester, Charlotte Eddy, Vishakha Tripathi, Virginia Attard. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucassen, Gillian Crawford, Donna McBride, Sarah Smalley. EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles, Elizabeth Bancroft and Lucia D’Mello are also supported by Cancer Research UK Grant C5047/A8385. Funding Information: Gynecologic Oncology Group (GOG): GOG’s participation was supported through funding provided by both intramural (Clinical Genetics Branch, DCEG) and extramural (Community Oncology and Prevention Trials Program, COPTRG) NCI programs, as well as by GOG’s Cancer Prevention and Control Committee. Funding Information: This work was supported by the European Community’s Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175). D.G.C. received a grant from the INSERM/INCa. J.S. is Chairholder of the Canada Research Chair in Oncogenetics. This work was supported by the LIGUE CONTRE LE CANCER (S.M. and O.M.S.) and by the Canadian Institutes of Health Research for the ‘CIHR Team in Familial Risks of Breast Cancer’ program and by the Canadian Breast Cancer Research Alliance-grant #019511. D.S. holds the Franc¸ois-Karl Viau Chair in Pediatric Oncogenomics and is a scholar of the Fonds de la Recherche en Santé du Québec (FRSQ). A.C.A. is a CR-UK Senior Cancer Research Fellow, D.F.E. is CR-UK Principal Research Fellow and G.C.T. is a NHMRC Senior Principal Research Fellow. Funding Information: Kathleen Cuningham Foundation Consortium for research into Familial Breast cancer (kConFab): We wish 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 (funded by NHMRC grants 145684, 288704 and 454508) for their contributions to this resource, and the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation, the National Health and Medical Research Council (NHMRC) and by the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. A.B.S. and G.C.-T. are supported by a NHMRC Senior Research and Principal Research Fellowships, respectively. Funding Information: University of Pennsylvania (UPENN): We acknowledge support by the Breast Cancer Research Foundation to K.L.N., by the Susan G. Komen Foundation to S.M.D., and by R01-CA083855 and R01-CA102776 to T.R.R. for the MAGIC consortium. Funding Information: National Cancer Institute (NCI): The research of Drs PL Mai and MH Greene was supported by the Intramural Research Program of the US National Cancer Institute, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc., Rockville, MD. Funding Information: Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO) study: Cancer Genetics Network ‘Groupe Gén-eétique et Cancer’, Fédération Nationale des Centres de Lutte Contre le Cancer, France. The study was supported by the Ligue National Contre le Cancer; Association for International Cancer Research Grant (AICR-07-0454); and the Association ‘Le cancer du sein, parlons-en!’ Award. We wish to thank all the GEMO collaborating groups for their contribution to this study. GEMO Collaborating Centers are: Coordinating Centres, Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Centre Hospitalier Universitaire de Lyon/ Centre Léon Bérard, & Equipe «Génétique du cancer du sein», Centre de Recherche en Cancérologie de Lyon, Lyon: Olga Sinilnikova, Laure Barjhoux, Carole Verny-Pierre, Sophie Giraud, Mélanie Léone, Sylvie Mazoyer; and Service de Génétique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Bruno Buecher, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, Carole Tirapo, Antoine de Pauw. Institut Gustave Roussy, Villejuif: Brigitte Bressac-de-Paillerets, Audrey Remenieras, Véronique Byrde, Olivier Caron, Gilbert Lenoir. Centre Jean Perrin, Clermont – Ferrand: Yves-Jean Bignon, Nancy Uhr-hammer. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona. Centre Franc¸ois Baclesse, Caen: Agnès Hardouin, Pascaline Berthet. Institut Paoli Calmettes, Marseille: Hagay Sobol, Violaine Bourdon, Tetsuro Noguchi, Franc¸ois Eisinger. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier. CHU de Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier, Pascal Pujol. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Franc¸oise Révillion, Philippe Vennin, Claude Adenis. Hôpital René Huguenin/Institut Curie, St Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange, Catherine Nogues. Centre Paul Strauss, Strasbourg: Danièle Muller, Jean-Pierre Fricker. Institut Bergonié, Bordeaux: Michel Longy, Nicolas Sevenet. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guimbaud, Laurence Gladieff, Viviane Feillel. CHU de Grenoble: Dominique Leroux, Hélène Dreyfus, Christine Rebischung. CHU de Dijon: Fanny Coron, Laurence Faivre. CHU de St-Etienne: Fabienne Prieur, Marine Lebrun. Hôtel Dieu Centre Hospita-lier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacas-sagne, Nice: Marc Frénay. CHU de Limoges: Laurence Vénat-Bouvet. CHU de Nantes: Capucine Delnatte. CHU Bre-tonneau, Tours: Isabelle Mortemousque. Creighton University, Omaha, USA: Henry T. Lynch, Carrie L. Snyder. Funding Information: Helsinki Breast Cancer Study (HEBCS): The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society and the Sigrid Juselius Foundation. HEBCS thanks Drs Kristiina Aittomäki, Carl Blomqvist and Tuomas Heikkinen and RN Irja Erkkilä for their help with the patient data and samples. Funding Information: The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC): GC-HBOC is supported by a grant of the German Cancer Aid (grant 107054). We thank Raymonda Varon-Mateeva (Center Berlin), Karin Kast (Center Dresden), Sabine Preisler-Adams (Center Münster), Helmut Deissler (Center Ulm), Ines Schönbuchner (Center Würzburg), Wolfram Heinritz (Center Leipzig) and Dieter Schäfer (Center Frankfurt) for providing samples and clinical data and Juliane Köhler for her excellent technical assistance.
PY - 2011/12/1
Y1 - 2011/12/1
N2 - 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 5 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.
AB - 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 5 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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U2 - 10.1093/hmg/ddr388
DO - 10.1093/hmg/ddr388
M3 - Article
C2 - 21890493
AN - SCOPUS:81255190718
SN - 0964-6906
VL - 20
SP - 4732
EP - 4747
JO - Human molecular genetics
JF - Human molecular genetics
IS - 23
ER -