Abstract
Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 × 3 10-3) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutationcarriersfromninecenters. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (Ptrend < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR 5 0.78, 95% CI: 0.69-0.90, Ptrend = 3.6 × 10-4 and HR 5 1.25, 95% CI: 1.10-1.41, Ptrend = 4.2 × 10-4), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR 5 1.55, 95% CI: 1.25-1.92, Ptrend 5 6 × 10-5 and HR 5 1.37, 95% CI: 1.16-1.62, Ptrend 5 1.7 × 10-4). The magnitude and direction of the associations were consistent with the original GWAS. In sub-sequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.
Original language | English (US) |
---|---|
Article number | ddq174 |
Pages (from-to) | 2886-2897 |
Number of pages | 12 |
Journal | Human molecular genetics |
Volume | 19 |
Issue number | 14 |
DOIs | |
State | Published - Apr 23 2010 |
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
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In: Human molecular genetics, Vol. 19, No. 14, ddq174, 23.04.2010, p. 2886-2897.
Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Common variants associated with breast cancer in genome-wide association studies are modifiers of breast cancer risk in BRCA1 and BRCA2 mutation carriers
AU - Wang, Xianshu
AU - Pankratz, V. Shane
AU - Fredericksen, Zachary
AU - Tarrell, Robert
AU - Karaus, Mary
AU - McGuffog, Lesley
AU - Pharaoh, Paul D.P.
AU - Ponder, Bruce A.J.
AU - Dunning, Alison M.
AU - Peock, Susan
AU - Cook, Margaret
AU - Oliver, Clare
AU - Frost, Debra
AU - Sinilnikova, Olga M.
AU - Stoppa-Lyonnet, Dominique
AU - Mazoyer, Sylvie
AU - Houdayer, Claude
AU - Hogervorst, Frans B.L.
AU - Hooning, Maartje J.
AU - Ligtenberg, Marjolijn J.
AU - Spurdle, Amanda
AU - Chenevix-Trench, Georgia
AU - Schmutzler, Rita K.
AU - Wappenschmidt, Barbara
AU - Engel, Christoph
AU - Meindl, Alfons
AU - Domchek, Susan M.
AU - Nathanson, Katherine L.
AU - Rebbeck, Timothy R.
AU - Singer, Christian F.
AU - Gschwantler-Kaulich, Daphne
AU - Dressler, Catherina
AU - Fink, Anneliese
AU - Szabo, Csilla I.
AU - Zikan, Michal
AU - Foretova, Lenka
AU - Claes, Kathleen
AU - Thomas, Gilles
AU - Hoover, Robert N.
AU - Hunter, David J.
AU - Chanock, Stephen J.
AU - Easton, Douglas F.
AU - Antoniou, Antonis C.
AU - Couch, Fergus J.
N1 - Funding Information: The work was supported by R01 grants (CA122340, CA128978) and a Breast Cancer Specialized Program of Research Excellence grant [P50 CA116201 (SPORE)] from the National Cancer Institute at the National Institutes of Health, an award from the Breast Cancer Research Foundation and an award from the Komen Race for the Cure Foundation to F.J.C. The UK1 GWAS was funded by a Cancer Research UK award to D.F.E. The CGEMS GWAS was funded by intramural funds from the National Institutes of Health. Funding Information: Csilla Szabo (Mayo Clinic College of Medicine, Rochester, MN); Michal Zikan, Petr Pohlreich, Zdenek Kleibl (First Faculty of Medicine, Charles University, Prague, Czech Republic); Lenka Foretova, Eva Machackova, Miroslava Lukesova (Masaryk Memorial Cancer Institute, Brno, Czech Republic); Kathleen Claes, Kim De Leeneer, Bruce Poppe, Anne De Paepe (Ghent University, Ghent, Belgium). Csilla Szabo was supported by Susan G. Komen Foundation Basic, Clinical, and Translational Research grant (BCTR0402923) and the Mayo Rochester Early Career Development Award for Non-Clinician Scientists; Michal Zikan by the Grant Agency of the Czech republic grant No. 301/08/P103. Lenka Forebova through the Ministry of Health of the CR grant MZ0 MOU 2005, Kathleen Claes by grant 1.5.150.07 from the Fund for Scientific Research Flanders (FWO), Anne De Peepe by grant 12051203 from the Ghent University. Bruce Poppe is Senior Clinical Investigator of the Fund for Scientific Research of Flanders (FWO—Vlaanderen). Funding Information: Unité Mixte de Génétique Constitutionnelle des Cancers Fré-quents, Centre Hospitalier Universitaire de Lyon/Centre Léon Bérard, and UMR5201 CNRS, Universitéde Lyon, Lyon: Olga Sinilnikova, Laure Barjhoux, Sophie Giraud, Mélanie Léone, Sylvie Mazoyer. INSERM U509, Service de Génétique Oncologique, Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars, Claude Houdayer, Virginie Moncoutier, Muriel Belotti, 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 Uhrhammer. Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona. Centre Franc¸ois Baclesse, Caen: Agnès Hardouin, Pascaline Berthet. Institut Paoli Calm-ettes, Marseille: Hagay Sobol, Violaine Bourdon, Franc¸ois Eisinger. Groupe Hospitalier Pitié-Salpétrière, Paris: Florence Coulet, Chrystelle Colas, Florent Soubrier. CHU de Arnaud-de-Villeneuve, Montpellier: Isabelle Coupier. Centre Oscar Lambret, Lille: Jean-Philippe Peyrat, Joëlle Fournier, Franc¸oise Révillion, Philippe Vennin, Claude Adenis. Centre René Huguenin, St Cloud: Etienne Rouleau, Rosette Lidereau, Liliane Demange, Catherine Nogues. Centre Paul Strauss, Strasbourg: Danièle Muller, Jean-Pierre Fricker. Institut Ber-gonié, Bordeaux: Michel Longy, Nicolas Sevenet. Institut Claudius Regaud, Toulouse: Christine Toulas, Rosine Guim-baud, Laurence Gladieff, Viviane Feillel. CHU de Grenoble: Dominique Leroux, Hélène Dreyfus, Christine Rebischung. CHU de Dijon: Cécile Cassini, Laurence Olivier-Faivre. CHU de St-Etienne: Fabienne Prieur. Hôtel Dieu Centre Hos-pitalier, Chambéry: Sandra Fert Ferrer. Centre Antoine Lacas-sagne, Nice: Marc Frénay. CHU de Limoges: Laurence Vénat-Bouvet. Creighton University, Omaha, USA: Henry T. Lynch. We wish to thank all the GEMO collaborating members for their contribution to this study. The GEMO study was supported by the Ligue National Contre le Cancer and the Association ‘Le cancer du sein, parlons-en!’ Award. Funding Information: Coordinating center: Netherlands Cancer Institute, Amsterdam: Frans Hogervorst, Senno Verhoef, Anouk Pijpe, Laura van ’t Veer, Flora van Leeuwen, Matti Rookus. Erasmus Medical Center, Rotterdam: Margriet Collée, Ans van den Ouweland, Mieke Kriege, Mieke Schutte, Maartje Hooning, Caroline Seynaeve. Leiden University Medical Center, Leiden: Christi van Asperen, Juul Wijnen, Maaike Vreeswijk, Rob Tollenaar, Peter Devilee. Radboud University Nijmegen Medical Center, Nijmegen: Marjolijn Ligtenberg, Nicoline Hoogerbrugge. University Medical Center Utrecht, Utrecht: Margreet Ausems, Rob van der Luijt. Amsterdam Medical Center: Cora Aalfs, Theo van Os. VU University Medical Center, Amsterdam: Hans Gille, Quinten Waisfisz, Hanne Meijers-Heijboer. University Hospital Maastricht, Maastricht: Encarna Gomez-Garcia, Kees van Roozendaal, Marinus Blok. University Medical Center Groningen University: Jan Ooster-wijk, Annemieke van der Hout, Marian Mourits. The Netherlands Foundation for the detection of hereditary tumours, Leiden, the Netherlands: Hans Vasen. The HEBON study is supported by the Dutch Cancer Society grants NKI 1998-1854, NKI 2004-3088 and NKI 2007-3756. Funding Information: 1Department of Laboratory Medicine and Pathology and 2Health Sciences Research, Mayo Clinic, Rochester, MN, USA, 3Department of Public Health and Primary Care, Cancer Research UK Genetic Epidemiology Unit and 4Department of Oncology, University of Cambridge, Cambridge, UK, 5Unité Mixte de Génétique Constitutionnelle des Cancers Fréquents, Hospices Civils de Lyon/Centre Léon Bérard, Lyon, France, 6INSERM U509, Service de Génétique Oncologique, Institut Curie, Université Paris-Descartes, Paris, France, 7Equipe labellisée LIGUE 2008, UMR5201 CNRS, Centre Léon Bérard, Université de Lyon, Lyon, France, 8Department of Pathology, Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The Netherlands, 9Department of Medical Oncology, Rotterdam Family Cancer Clinic, Erasmus, The Netherlands, 10Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands, 11Queensland Institute of Medical Research, Brisbane, QLD 4029, Australia, 12kConFab (Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer), Peter MacCallum Cancer Institute, Melbourne, VIC 3002, Australia, 13Center of Familial Breast and Ovarian Cancer, University Hospital of Cologne, Cologne, Germany, 14Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany, 15Department of Obstetrics and Gynaecology, Klinikum rechts der Isar, Technical University, Munich, Germany, 16University of Pennsylvania, Philadelphia, PA, USA, 17Medical University of Vienna, Vienna, Austria, 18Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic, 19Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic, 20Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium, 21Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA, 22Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, USA, 23Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA and 24Advanced Technology Center, National Cancer Institute, Gaithersburg, MD, USA Funding Information: We thank all families for providing samples for this study. This work was supported by grants from the German Cancer Aid (Grant numbers 107054 and 107353). Funding Information: Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Emma Kivuva, Anne Searle, Selina Goodman. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday, Nicola Bradshaw, Lesley Snadden, Mark Longmuir, Catherine Watt. South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt, Gabriella Pichert, Caroline Langman. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Julian Barwell. Yorkshire Regional Genetics Service, Leeds: Carol Chu, Tim Bishop, Julie Miller. Merseyside and Cheshire Clinical Genetics Service, Liverpool: Ian Ellis. Manchester Regional Genetics Service, Manchester: D. Gareth Evans, Fiona Lalloo, Felicity Holt. North East Thames Regional Genetics Service, NE Thames: Alison Male, Anne Robinson. Nottingham Centre for Medical Genetics, Nottingham: Carol Gardiner. Northern Clinical Genetics Service, Newcastle: Fiona Douglas, Oonagh Claber. Oxford Regional Genetics Service, Oxford: Lisa Walker, Diane McLeod. 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, Anita Mitra. 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. Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton: Diana Eccles, Anneke Lucas-sen, Gillian Crawford, Emma Tyler, Donna McBride. The EMBRACE study was funded by Cancer Research UK. S.P. is funded by Cancer Research-UK Grants C1287/A10118 and C1287/A8874. D.G.E. and F.L. 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. R.E./E.B./L.D’M. are also supported by Cancer Research UK Grant C5047/A8385. A.C.A. is a Cancer Research UK Senior Cancer Research Fellow. D.F.E. is a Principal Research Fellow of Cancer Research UK. Funding Information: 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 Senior and Senior Principal Research Fellows, respectively, of the NHMRC.
PY - 2010/4/23
Y1 - 2010/4/23
N2 - Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 × 3 10-3) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutationcarriersfromninecenters. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (Ptrend < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR 5 0.78, 95% CI: 0.69-0.90, Ptrend = 3.6 × 10-4 and HR 5 1.25, 95% CI: 1.10-1.41, Ptrend = 4.2 × 10-4), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR 5 1.55, 95% CI: 1.25-1.92, Ptrend 5 6 × 10-5 and HR 5 1.37, 95% CI: 1.16-1.62, Ptrend 5 1.7 × 10-4). The magnitude and direction of the associations were consistent with the original GWAS. In sub-sequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.
AB - Recent studies have identified single nucleotide polymorphisms (SNPs) that significantly modify breast cancer risk in BRCA1 and BRCA2 mutation carriers. Since these risk modifiers were originally identified as genetic risk factors for breast cancer in genome-wide association studies (GWASs), additional risk modifiers for BRCA1 and BRCA2 may be identified from promising signals discovered in breast cancer GWAS. A total of 350 SNPs identified as candidate breast cancer risk factors (P < 1 × 3 10-3) in two breast cancer GWAS studies were genotyped in 3451 BRCA1 and 2006 BRCA2 mutationcarriersfromninecenters. Associations with breast cancer risk were assessed using Cox models weighted for penetrance. Eight SNPs in BRCA1 carriers and 12 SNPs in BRCA2 carriers, representing an enrichment over the number expected, were significantly associated with breast cancer risk (Ptrend < 0.01). The minor alleles of rs6138178 in SNRPB and rs6602595 in CAMK1D displayed the strongest associations in BRCA1 carriers (HR 5 0.78, 95% CI: 0.69-0.90, Ptrend = 3.6 × 10-4 and HR 5 1.25, 95% CI: 1.10-1.41, Ptrend = 4.2 × 10-4), whereas rs9393597 in LOC134997 and rs12652447 in FBXL7 showed the strongest associations in BRCA2 carriers (HR 5 1.55, 95% CI: 1.25-1.92, Ptrend 5 6 × 10-5 and HR 5 1.37, 95% CI: 1.16-1.62, Ptrend 5 1.7 × 10-4). The magnitude and direction of the associations were consistent with the original GWAS. In sub-sequent risk assessment studies, the loci appeared to interact multiplicatively for breast cancer risk in BRCA1 and BRCA2 carriers. Promising candidate SNPs from GWAS were identified as modifiers of breast cancer risk in BRCA1 and BRCA2 carriers. Upon further validation, these SNPs together with other genetic and environmental factors may improve breast cancer risk assessment in these populations.
UR - http://www.scopus.com/inward/record.url?scp=77954500544&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77954500544&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddq174
DO - 10.1093/hmg/ddq174
M3 - Article
C2 - 20418484
AN - SCOPUS:77954500544
SN - 0964-6906
VL - 19
SP - 2886
EP - 2897
JO - Human molecular genetics
JF - Human molecular genetics
IS - 14
M1 - ddq174
ER -