Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Antonis C. Antoniou; Amanda B. Spurdle; Olga M. Sinilnikova; Sue Healey; Karen A. Pooley; Rita K. Schmutzler; Beatrix Versmold; Christoph Engel; Alfons Meindl; Norbert Arnold; Wera Hofmann; Christian Sutter; Dieter Niederacher; Helmut Deissler; Trinidad Caldes; Kati Kämpjärvi; Heli Nevanlinna; Jacques Simard; Jonathan Beesley; Xiaoqing Chen; Susan L. Neuhausen; Timothy R. Rebbeck; Theresa Wagner; Henry T. Lynch; Claudine Isaacs; Jeffrey Weitzel; Patricia A. Ganz; Mary B. Daly; Gail Tomlinson; Olufunmilayo I. Olopade; Joanne L. Blum; Fergus J. Couch; Paolo Peterlongo; Siranoush Manoukian; Monica Barile; Paolo Radice; Csilla I. Szabo; Lutecia H.Mateus Pereira; Mark H. Greene; Gad Rennert; Flavio Lejbkowicz; Ofra Barnett-Griness; Irene L. Andrulis; Hilmi Ozcelik; Anne Marie Gerdes; Maria A. Caligo; Yael Laitman; Bella Kaufman; Roni Milgrom; Eitan Friedman; Susan M. Domchek; Katherine L. Nathanson; Ana Osorio; Gemma Llort; Roger L. Milne; Javier Benítez; Ute Hamann; Frans B.L. Hogervorst; Peggy Manders; Marjolijn J.L. Ligtenberg; Ans M.W. van den Ouweland; Susan Peock; Margaret Cook; Radka Platte; D. Gareth Evans; Rosalind Eeles; Gabriella Pichert; Carol Chu; Diana Eccles; Rosemarie Davidson; Fiona Douglas; Andrew K. Godwin; Laure Barjhoux; Sylvie Mazoyer; Hagay Sobol; Violaine Bourdon; François Eisinger; Agnès Chompret; Corinne Capoulade; Brigitte Bressac-de Paillerets; Gilbert M. Lenoir; Marion Gauthier-Villars; Claude Houdayer; Dominique Stoppa-Lyonnet; Georgia Chenevix-Trench; Douglas F. Easton

doi:10.1016/j.ajhg.2008.02.008

Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

Antonis C. Antoniou, Amanda B. Spurdle, Olga M. Sinilnikova, Sue Healey, Karen A. Pooley, Rita K. Schmutzler, Beatrix Versmold, Christoph Engel, Alfons Meindl, Norbert Arnold, Wera Hofmann, Christian Sutter, Dieter Niederacher, Helmut Deissler, Trinidad Caldes, Kati Kämpjärvi, Heli Nevanlinna, Jacques Simard, Jonathan Beesley, Xiaoqing ChenSusan L. Neuhausen, Timothy R. Rebbeck, Theresa Wagner, Henry T. Lynch, Claudine Isaacs, Jeffrey Weitzel, Patricia A. Ganz, Mary B. Daly, Gail Tomlinson, Olufunmilayo I. Olopade, Joanne L. Blum, Fergus J. Couch, Paolo Peterlongo, Siranoush Manoukian, Monica Barile, Paolo Radice, Csilla I. Szabo, Lutecia H.Mateus Pereira, Mark H. Greene, Gad Rennert, Flavio Lejbkowicz, Ofra Barnett-Griness, Irene L. Andrulis, Hilmi Ozcelik, Anne Marie Gerdes, Maria A. Caligo, Yael Laitman, Bella Kaufman, Roni Milgrom, Eitan Friedman, Susan M. Domchek, Katherine L. Nathanson, Ana Osorio, Gemma Llort, Roger L. Milne, Javier Benítez, Ute Hamann, Frans B.L. Hogervorst, Peggy Manders, Marjolijn J.L. Ligtenberg, Ans M.W. van den Ouweland, Susan Peock, Margaret Cook, Radka Platte, D. Gareth Evans, Rosalind Eeles, Gabriella Pichert, Carol Chu, Diana Eccles, Rosemarie Davidson, Fiona Douglas, Andrew K. Godwin, Laure Barjhoux, Sylvie Mazoyer, Hagay Sobol, Violaine Bourdon, François Eisinger, Agnès Chompret, Corinne Capoulade, Brigitte Bressac-de Paillerets, Gilbert M. Lenoir, Marion Gauthier-Villars, Claude Houdayer, Dominique Stoppa-Lyonnet, Georgia Chenevix-Trench, Douglas F. Easton

Research output: Contribution to journal › Article › peer-review

223 Scopus citations

Abstract

Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, p_trend = 1.7 × 10^-8 and HR = 1.12, 95% CI: 1.02-1.24, p_trend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, p_trend = 5 × 10^-5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

Original language	English (US)
Pages (from-to)	937-948
Number of pages	12
Journal	American journal of human genetics
Volume	82
Issue number	4
DOIs	https://doi.org/10.1016/j.ajhg.2008.02.008
State	Published - Apr 11 2008

ASJC Scopus subject areas

Genetics
Genetics(clinical)

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10.1016/j.ajhg.2008.02.008

Cite this

Antoniou, A. C., Spurdle, A. B., Sinilnikova, O. M., Healey, S., Pooley, K. A., Schmutzler, R. K., Versmold, B., Engel, C., Meindl, A., Arnold, N., Hofmann, W., Sutter, C., Niederacher, D., Deissler, H., Caldes, T., Kämpjärvi, K., Nevanlinna, H., Simard, J., Beesley, J., ... Easton, D. F. (2008). Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. American journal of human genetics, 82(4), 937-948. https://doi.org/10.1016/j.ajhg.2008.02.008

Antoniou, AC, Spurdle, AB, Sinilnikova, OM, Healey, S, Pooley, KA, Schmutzler, RK, Versmold, B, Engel, C, Meindl, A, Arnold, N, Hofmann, W, Sutter, C, Niederacher, D, Deissler, H, Caldes, T, Kämpjärvi, K, Nevanlinna, H, Simard, J, Beesley, J, Chen, X, Neuhausen, SL, Rebbeck, TR, Wagner, T, Lynch, HT, Isaacs, C, Weitzel, J, Ganz, PA, Daly, MB, Tomlinson, G, Olopade, OI, Blum, JL, Couch, FJ, Peterlongo, P, Manoukian, S, Barile, M, Radice, P, Szabo, CI, Pereira, LHM, Greene, MH, Rennert, G, Lejbkowicz, F, Barnett-Griness, O, Andrulis, IL, Ozcelik, H, Gerdes, AM, Caligo, MA, Laitman, Y, Kaufman, B, Milgrom, R, Friedman, E, Domchek, SM, Nathanson, KL, Osorio, A, Llort, G, Milne, RL, Benítez, J, Hamann, U, Hogervorst, FBL, Manders, P, Ligtenberg, MJL, van den Ouweland, AMW, Peock, S, Cook, M, Platte, R, Evans, DG, Eeles, R, Pichert, G, Chu, C, Eccles, D, Davidson, R, Douglas, F, Godwin, AK, Barjhoux, L, Mazoyer, S, Sobol, H, Bourdon, V, Eisinger, F, Chompret, A, Capoulade, C, Bressac-de Paillerets, B, Lenoir, GM, Gauthier-Villars, M, Houdayer, C, Stoppa-Lyonnet, D, Chenevix-Trench, G & Easton, DF 2008, 'Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers', American journal of human genetics, vol. 82, no. 4, pp. 937-948. https://doi.org/10.1016/j.ajhg.2008.02.008

@article{9069908986aa4de59bebae780ff00e62,

title = "Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers",

abstract = "Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, ptrend = 1.7 × 10-8 and HR = 1.12, 95% CI: 1.02-1.24, ptrend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, ptrend = 5 × 10-5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.",

author = "Antoniou, {Antonis C.} and Spurdle, {Amanda B.} and Sinilnikova, {Olga M.} and Sue Healey and Pooley, {Karen A.} and Schmutzler, {Rita K.} and Beatrix Versmold and Christoph Engel and Alfons Meindl and Norbert Arnold and Wera Hofmann and Christian Sutter and Dieter Niederacher and Helmut Deissler and Trinidad Caldes and Kati K{\"a}mpj{\"a}rvi and Heli Nevanlinna and Jacques Simard and Jonathan Beesley and Xiaoqing Chen and Neuhausen, {Susan L.} and Rebbeck, {Timothy R.} and Theresa Wagner and Lynch, {Henry T.} and Claudine Isaacs and Jeffrey Weitzel and Ganz, {Patricia A.} and Daly, {Mary B.} and Gail Tomlinson and Olopade, {Olufunmilayo I.} and Blum, {Joanne L.} and Couch, {Fergus J.} and Paolo Peterlongo and Siranoush Manoukian and Monica Barile and Paolo Radice and Szabo, {Csilla I.} and Pereira, {Lutecia H.Mateus} and Greene, {Mark H.} and Gad Rennert and Flavio Lejbkowicz and Ofra Barnett-Griness and Andrulis, {Irene L.} and Hilmi Ozcelik and Gerdes, {Anne Marie} and Caligo, {Maria A.} and Yael Laitman and Bella Kaufman and Roni Milgrom and Eitan Friedman and Domchek, {Susan M.} and Nathanson, {Katherine L.} and Ana Osorio and Gemma Llort and Milne, {Roger L.} and Javier Ben{\'i}tez and Ute Hamann and Hogervorst, {Frans B.L.} and Peggy Manders and Ligtenberg, {Marjolijn J.L.} and {van den Ouweland}, {Ans M.W.} and Susan Peock and Margaret Cook and Radka Platte and Evans, {D. Gareth} and Rosalind Eeles and Gabriella Pichert and Carol Chu and Diana Eccles and Rosemarie Davidson and Fiona Douglas and Godwin, {Andrew K.} and Laure Barjhoux and Sylvie Mazoyer and Hagay Sobol and Violaine Bourdon and Fran{\c c}ois Eisinger and Agn{\`e}s Chompret and Corinne Capoulade and {Bressac-de Paillerets}, Brigitte and Lenoir, {Gilbert M.} and Marion Gauthier-Villars and Claude Houdayer and Dominique Stoppa-Lyonnet and Georgia Chenevix-Trench and Easton, {Douglas F.}",

note = "Funding Information: German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC). GC-HBOC is supported by a grant of the German Cancer Aid (grant 107054) and the Center for Molecular Medicine Cologne (grant TV93) to R.K.S. Funding Information: Deutsches Krebsforschungszentrum (DKFZ) study. 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 and Michael Gilbert for expert technical assistance. Funding Information: Ontario Cancer Genetics Network (OCGN) study. We thank Mona Gill for excellent technical assistance and acknowledge funding from Cancer Care Ontario and the National Cancer Institute of Canada with funds from the Terry Fox Run. Funding Information: DNA-HEBON. The following are DNA-HEBON collaborating centers, Netherlands. Coordinating center, Netherlands Cancer Institute, Amsterdam: Frans Hogervorst, Peggy Manders, Matti Rookus, Flora van Leeuwen, Laura van 't Veer, and Senno Verhoef. Erasmus Medical Center, Rotterdam: Ans van den Ouweland, Margriet Coll{\'e}e, and Jan Klijn. Leiden University Medical Center, Leiden: Juul Wijnen and Christi van Asperen. Radboud University Nijmegen Medical Center, Nijmegen: Marjolijn Ligtenberg and Nicoline Hoogerbrugge. VU University Medical Center, Amsterdam: Hans Gille and Hanne Meijers-Heijboer. University Hospital Maastricht, Maastricht: Kees van Roozendaal, Rien Blok, and Encarna Gomez-Garcia. The DNA-HEBON study is part of the HEBON study (HEriditary Breast and Ovarian study Netherlands) andis supported by Dutch Cancer Society grants NKI2004-3088 and NKI2007-3756. Funding Information: EMBRACE. M.C., S.P., and EMBRACE are funded by Cancer Research-UK. D.F.E. is the PI of the study. The following are EMBRACE collaborating centers. Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, and Alexandra Bignell. North of Scotland Regional Genetics Service, Aberdeen: Neva Haites, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole and Carole McKeown. South West Regional Genetics Service, Bristol: Alan Donaldson. East Anglian Regional Genetics Service, Cambridge: Joan Paterson. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, and Mark Rogers. St James's Hospital, Dublin and National Centre for Medical Genetics, Dublin: Peter Daly and David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous and Michael Steel. Peninsula Clinical Genetics Service. Exeter: Carole Brewer and Julia Rankin. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson and Victoria Murday. South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt and Gabriella Pichert. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Richard Trembath. Yorkshire Regional Genetics Service, Leeds: Tim Bishop and Carol Chu. Merseyside and Cheshire Clinical Genetics Service, Liverpool: Ian Ellis. Manchester Regional Genetics Service, Manchester: D. Gareth Evans, Fiona Lalloo, and Andrew Shenton. North East Thames Regional Genetics Service, NE Thames: Alison Male, James Mackay, and Anne Robinson. Nottingham Centre for Medical Genetics, Nottingham: Carol Gardiner. Northern Clinical Genetics Service, Newcastle: Fiona Douglas and John Burn. Oxford Regional Genetics Service, Oxford: Lucy Side, LIsa Walker, and Sarah Durell. Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Rosalind Eeles. North Trent Clinical Genetics Service, Sheffield: Jackie Cook and Oliver Quarrell. South West Thames Regional Genetics Service, London: Shirley Hodgson. Wessex Clinical Genetics Service. Southampton: Diana Eccles and Anneke Lucassen. Funding Information: Helsinki Breast Cancer Study (HEBCS). HEBCS was supported by the Academy of Finland (110663), Helsinki University Central Hospital Research Fund, the Sigrid Juselius Fund, and the Finnish Cancer Society. We thank Tuomas Heikkinen for his contribution in the molecular analyses and Kristiina Aittom{\"a}ki, Kirsimari Aaltonen, and Carl Blomqvist for their help in patient sample and data collection. Funding Information: Odense University Hospital (OUH) study. The Danish Cancer Research Fund supported the Danish group at Odense University Hospital. Mads Thomassen is greatly acknowledged for performing the genotyping of the Danish samples. Funding Information: Interdisciplinary Health Research International Team Breast Cancer Susceptibility (INHERIT). Jacques Simard, Francine Durocher, Rachel Laframboise, and Marie Plante, Centre Hospitalier Universitaire de Quebec & Laval University, Quebec, Canada; Peter Bridge, and Jilian Parboosingh Molecular Diagnostic Laboratory, Alberta Children's Hospital, Calgary, Canada; Jocelyne Chiquette, H{\^o}pital du Saint-Sacrement, Quebec, Canada; Bernard Lesperance and Roxanne Pichette, H{\^o}pital du Sacr{\'e}-C{\oe}ur de Montr{\'e}al, Quebec, Canada. This work was supported by the Canadian Institutes of Health Research for the INHERIT BRCAs program, the CURE Foundation, and the Fonds de la recherche en Sant{\'e} du Quebec/Reseau de Medecine Genetique Appliquee. Funding Information: University of Pennsylvania (UPENN) study. K.L.N. is supported by the Breast Cancer Research Foundation (BCRF). S.M.D. is supported by QVC Network, the Fashion Footwear Association of New York, and the Marjorie B. Cohen Foundation. Funding Information: Modifier Study of Quantitative Effects on Disease (Mod-SQuaD). C.I.S. is partially supported by a Susan G. Komen Foundation Basic. Clinical, and Translational Research Grant (BCTR0402923). Research Project of the Ministry of Education, Youth and Sports of the Czech Republic No. MSM0021620808 to Michal Zikan, Zdenek Kleibl, and Petr Pohlreich. We acknowledge the contributions of Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University Prague, Czech Republic) and Lenka Foretova, Machakova Eva, and Lukesova Miroslava (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic). Funding Information: Milan Breast Cancer Study Group (MBCSG). MBCSG is supported by Fondazione Italiana per la Ricerca sul Cancro (FIRC, Special Project “Hereditary tumors”). MBCSG acknowledges Marco Pierotti of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and Bernardo Bonanni of the Istituto Europeo di Oncologia, Milan, italy. Funding Information: Modifiers and Genetics in Cancer (MAGIC). Support was received from NIH grants R01-CA083855 and R01-CA74415 (to S.L.N.) and grants R01-CA102776 and R01-CA083855 (to T.R.R.). Support was also received from grant NCI P30 CA51008-12 (to C.I.). This article was supported by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services. Support was also given by the National Institutes of Health through grant #1U01 CA 86389. Henry Lynch's work is partially funded through the Charles F. and Mary C. Heider Chair in Cancer Research, which he holds at Creighton University. The hereditary cancer registry at City of Hope (J.W.) is supported in part by a General Clinical Research Center grant (M01 RR00043) awarded by the NIH to the City of Hope National Medical Center, Duarte, California. Funding Information: Fox Chase Cancer Center (FCCC). A.K.G. was funded by SPORE P-50 CA 83638, U01 CA69631, 5U01 CA113916, and the Eileen Stein Jacoby Fund. Funding Information: National Cancer Institute study (NCI). We acknowledge the contributions of Jeffery Struewing and Marbin A Pineda from the Laboratory of Population Genetics. Greene and Struewing were supported by funding from the Intramural Research Program of the National Cancer Institute. Their data-collection efforts were supported by contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. Funding Information: The Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab). We wish to thank Heather Thorne, Eveline Niedermayr, Helene Holland, 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 and 288704) for their contributions to this resource, as well as the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation and 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 a NHMRC Career Development awardee and a senior principal research fellow, respectively. Funding Information: Mayo Clinic Study (MAYO). The Mayo Clinic study was supported by the Breast Cancer Research Foundation (BCRF), U.S. Army Medical Research and Materiel Command (W81XWH-04-1-0588), the Mayo Clinic Breast Cancer SPORE (P50-CA116201), and NIH grant CA122340 to F.J.C. We wish to thank Noralane Lindor and Linda Wadum for their contributions. Funding Information: Spanish National Cancer Centre (CNIO). Thanks to Rosario Alonso, Alicia Barroso, and Guillermo Pita for their technical support. The samples studied at the CNIO were recruited by the Spanish Consortium for the Study of Genetic Modifiers of BRCA1 and BRCA2 (Spanish National Cancer Centre [Madrid], Sant Pau Hospital [Barcelona], Instituto Catal{\'a} d`Oncolog{\'i}a [Barcelona], Hospital Cl{\'i}nico San Carlos [Madrid], Valladolid University [Madrid], Cancer Research Centre [Salamanca], and Instituto Dexeus [Barcelona]) and the Instituto Demokritos. The work carried out at the CNIO was partly funded by grants from the Genome Spain, Mutual Madrile{\~n}a and Marat{\'o} Foundations. ",

year = "2008",

month = apr,

day = "11",

doi = "10.1016/j.ajhg.2008.02.008",

language = "English (US)",

volume = "82",

pages = "937--948",

journal = "American journal of human genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "4",

}

TY - JOUR

T1 - Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

AU - Antoniou, Antonis C.

AU - Spurdle, Amanda B.

AU - Sinilnikova, Olga M.

AU - Healey, Sue

AU - Pooley, Karen A.

AU - Schmutzler, Rita K.

AU - Versmold, Beatrix

AU - Engel, Christoph

AU - Meindl, Alfons

AU - Arnold, Norbert

AU - Hofmann, Wera

AU - Sutter, Christian

AU - Niederacher, Dieter

AU - Deissler, Helmut

AU - Caldes, Trinidad

AU - Kämpjärvi, Kati

AU - Nevanlinna, Heli

AU - Simard, Jacques

AU - Beesley, Jonathan

AU - Chen, Xiaoqing

AU - Neuhausen, Susan L.

AU - Rebbeck, Timothy R.

AU - Wagner, Theresa

AU - Lynch, Henry T.

AU - Isaacs, Claudine

AU - Weitzel, Jeffrey

AU - Ganz, Patricia A.

AU - Daly, Mary B.

AU - Tomlinson, Gail

AU - Olopade, Olufunmilayo I.

AU - Blum, Joanne L.

AU - Couch, Fergus J.

AU - Peterlongo, Paolo

AU - Manoukian, Siranoush

AU - Barile, Monica

AU - Radice, Paolo

AU - Szabo, Csilla I.

AU - Pereira, Lutecia H.Mateus

AU - Greene, Mark H.

AU - Rennert, Gad

AU - Lejbkowicz, Flavio

AU - Barnett-Griness, Ofra

AU - Andrulis, Irene L.

AU - Ozcelik, Hilmi

AU - Gerdes, Anne Marie

AU - Caligo, Maria A.

AU - Laitman, Yael

AU - Kaufman, Bella

AU - Milgrom, Roni

AU - Friedman, Eitan

AU - Domchek, Susan M.

AU - Nathanson, Katherine L.

AU - Osorio, Ana

AU - Llort, Gemma

AU - Milne, Roger L.

AU - Benítez, Javier

AU - Hamann, Ute

AU - Hogervorst, Frans B.L.

AU - Manders, Peggy

AU - Ligtenberg, Marjolijn J.L.

AU - van den Ouweland, Ans M.W.

AU - Peock, Susan

AU - Cook, Margaret

AU - Platte, Radka

AU - Evans, D. Gareth

AU - Eeles, Rosalind

AU - Pichert, Gabriella

AU - Chu, Carol

AU - Eccles, Diana

AU - Davidson, Rosemarie

AU - Douglas, Fiona

AU - Godwin, Andrew K.

AU - Barjhoux, Laure

AU - Mazoyer, Sylvie

AU - Sobol, Hagay

AU - Bourdon, Violaine

AU - Eisinger, François

AU - Chompret, Agnès

AU - Capoulade, Corinne

AU - Bressac-de Paillerets, Brigitte

AU - Lenoir, Gilbert M.

AU - Gauthier-Villars, Marion

AU - Houdayer, Claude

AU - Stoppa-Lyonnet, Dominique

AU - Chenevix-Trench, Georgia

AU - Easton, Douglas F.

N1 - Funding Information: German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC). GC-HBOC is supported by a grant of the German Cancer Aid (grant 107054) and the Center for Molecular Medicine Cologne (grant TV93) to R.K.S. Funding Information: Deutsches Krebsforschungszentrum (DKFZ) study. 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 and Michael Gilbert for expert technical assistance. Funding Information: Ontario Cancer Genetics Network (OCGN) study. We thank Mona Gill for excellent technical assistance and acknowledge funding from Cancer Care Ontario and the National Cancer Institute of Canada with funds from the Terry Fox Run. Funding Information: DNA-HEBON. The following are DNA-HEBON collaborating centers, Netherlands. Coordinating center, Netherlands Cancer Institute, Amsterdam: Frans Hogervorst, Peggy Manders, Matti Rookus, Flora van Leeuwen, Laura van 't Veer, and Senno Verhoef. Erasmus Medical Center, Rotterdam: Ans van den Ouweland, Margriet Collée, and Jan Klijn. Leiden University Medical Center, Leiden: Juul Wijnen and Christi van Asperen. Radboud University Nijmegen Medical Center, Nijmegen: Marjolijn Ligtenberg and Nicoline Hoogerbrugge. VU University Medical Center, Amsterdam: Hans Gille and Hanne Meijers-Heijboer. University Hospital Maastricht, Maastricht: Kees van Roozendaal, Rien Blok, and Encarna Gomez-Garcia. The DNA-HEBON study is part of the HEBON study (HEriditary Breast and Ovarian study Netherlands) andis supported by Dutch Cancer Society grants NKI2004-3088 and NKI2007-3756. Funding Information: EMBRACE. M.C., S.P., and EMBRACE are funded by Cancer Research-UK. D.F.E. is the PI of the study. The following are EMBRACE collaborating centers. Coordinating Centre, Cambridge: Susan Peock, Margaret Cook, and Alexandra Bignell. North of Scotland Regional Genetics Service, Aberdeen: Neva Haites, Helen Gregory. Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison. West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole and Carole McKeown. South West Regional Genetics Service, Bristol: Alan Donaldson. East Anglian Regional Genetics Service, Cambridge: Joan Paterson. Medical Genetics Services for Wales, Cardiff: Alexandra Murray, and Mark Rogers. St James's Hospital, Dublin and National Centre for Medical Genetics, Dublin: Peter Daly and David Barton. South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous and Michael Steel. Peninsula Clinical Genetics Service. Exeter: Carole Brewer and Julia Rankin. West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson and Victoria Murday. South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt and Gabriella Pichert. North West Thames Regional Genetics Service, Harrow: Huw Dorkins. Leicestershire Clinical Genetics Service, Leicester: Richard Trembath. Yorkshire Regional Genetics Service, Leeds: Tim Bishop and Carol Chu. Merseyside and Cheshire Clinical Genetics Service, Liverpool: Ian Ellis. Manchester Regional Genetics Service, Manchester: D. Gareth Evans, Fiona Lalloo, and Andrew Shenton. North East Thames Regional Genetics Service, NE Thames: Alison Male, James Mackay, and Anne Robinson. Nottingham Centre for Medical Genetics, Nottingham: Carol Gardiner. Northern Clinical Genetics Service, Newcastle: Fiona Douglas and John Burn. Oxford Regional Genetics Service, Oxford: Lucy Side, LIsa Walker, and Sarah Durell. Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Rosalind Eeles. North Trent Clinical Genetics Service, Sheffield: Jackie Cook and Oliver Quarrell. South West Thames Regional Genetics Service, London: Shirley Hodgson. Wessex Clinical Genetics Service. Southampton: Diana Eccles and Anneke Lucassen. Funding Information: Helsinki Breast Cancer Study (HEBCS). HEBCS was supported by the Academy of Finland (110663), Helsinki University Central Hospital Research Fund, the Sigrid Juselius Fund, and the Finnish Cancer Society. We thank Tuomas Heikkinen for his contribution in the molecular analyses and Kristiina Aittomäki, Kirsimari Aaltonen, and Carl Blomqvist for their help in patient sample and data collection. Funding Information: Odense University Hospital (OUH) study. The Danish Cancer Research Fund supported the Danish group at Odense University Hospital. Mads Thomassen is greatly acknowledged for performing the genotyping of the Danish samples. Funding Information: Interdisciplinary Health Research International Team Breast Cancer Susceptibility (INHERIT). Jacques Simard, Francine Durocher, Rachel Laframboise, and Marie Plante, Centre Hospitalier Universitaire de Quebec & Laval University, Quebec, Canada; Peter Bridge, and Jilian Parboosingh Molecular Diagnostic Laboratory, Alberta Children's Hospital, Calgary, Canada; Jocelyne Chiquette, Hôpital du Saint-Sacrement, Quebec, Canada; Bernard Lesperance and Roxanne Pichette, Hôpital du Sacré-Cœur de Montréal, Quebec, Canada. This work was supported by the Canadian Institutes of Health Research for the INHERIT BRCAs program, the CURE Foundation, and the Fonds de la recherche en Santé du Quebec/Reseau de Medecine Genetique Appliquee. Funding Information: University of Pennsylvania (UPENN) study. K.L.N. is supported by the Breast Cancer Research Foundation (BCRF). S.M.D. is supported by QVC Network, the Fashion Footwear Association of New York, and the Marjorie B. Cohen Foundation. Funding Information: Modifier Study of Quantitative Effects on Disease (Mod-SQuaD). C.I.S. is partially supported by a Susan G. Komen Foundation Basic. Clinical, and Translational Research Grant (BCTR0402923). Research Project of the Ministry of Education, Youth and Sports of the Czech Republic No. MSM0021620808 to Michal Zikan, Zdenek Kleibl, and Petr Pohlreich. We acknowledge the contributions of Michal Zikan, Petr Pohlreich and Zdenek Kleibl (Department of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University Prague, Czech Republic) and Lenka Foretova, Machakova Eva, and Lukesova Miroslava (Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic). Funding Information: Milan Breast Cancer Study Group (MBCSG). MBCSG is supported by Fondazione Italiana per la Ricerca sul Cancro (FIRC, Special Project “Hereditary tumors”). MBCSG acknowledges Marco Pierotti of the Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy and Bernardo Bonanni of the Istituto Europeo di Oncologia, Milan, italy. Funding Information: Modifiers and Genetics in Cancer (MAGIC). Support was received from NIH grants R01-CA083855 and R01-CA74415 (to S.L.N.) and grants R01-CA102776 and R01-CA083855 (to T.R.R.). Support was also received from grant NCI P30 CA51008-12 (to C.I.). This article was supported by revenue from Nebraska cigarette taxes awarded to Creighton University by the Nebraska Department of Health and Human Services. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the State of Nebraska or the Nebraska Department of Health and Human Services. Support was also given by the National Institutes of Health through grant #1U01 CA 86389. Henry Lynch's work is partially funded through the Charles F. and Mary C. Heider Chair in Cancer Research, which he holds at Creighton University. The hereditary cancer registry at City of Hope (J.W.) is supported in part by a General Clinical Research Center grant (M01 RR00043) awarded by the NIH to the City of Hope National Medical Center, Duarte, California. Funding Information: Fox Chase Cancer Center (FCCC). A.K.G. was funded by SPORE P-50 CA 83638, U01 CA69631, 5U01 CA113916, and the Eileen Stein Jacoby Fund. Funding Information: National Cancer Institute study (NCI). We acknowledge the contributions of Jeffery Struewing and Marbin A Pineda from the Laboratory of Population Genetics. Greene and Struewing were supported by funding from the Intramural Research Program of the National Cancer Institute. Their data-collection efforts were supported by contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. Funding Information: The Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab). We wish to thank Heather Thorne, Eveline Niedermayr, Helene Holland, 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 and 288704) for their contributions to this resource, as well as the many families who contribute to kConFab. kConFab is supported by grants from the National Breast Cancer Foundation and 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 a NHMRC Career Development awardee and a senior principal research fellow, respectively. Funding Information: Mayo Clinic Study (MAYO). The Mayo Clinic study was supported by the Breast Cancer Research Foundation (BCRF), U.S. Army Medical Research and Materiel Command (W81XWH-04-1-0588), the Mayo Clinic Breast Cancer SPORE (P50-CA116201), and NIH grant CA122340 to F.J.C. We wish to thank Noralane Lindor and Linda Wadum for their contributions. Funding Information: Spanish National Cancer Centre (CNIO). Thanks to Rosario Alonso, Alicia Barroso, and Guillermo Pita for their technical support. The samples studied at the CNIO were recruited by the Spanish Consortium for the Study of Genetic Modifiers of BRCA1 and BRCA2 (Spanish National Cancer Centre [Madrid], Sant Pau Hospital [Barcelona], Instituto Catalá d`Oncología [Barcelona], Hospital Clínico San Carlos [Madrid], Valladolid University [Madrid], Cancer Research Centre [Salamanca], and Instituto Dexeus [Barcelona]) and the Instituto Demokritos. The work carried out at the CNIO was partly funded by grants from the Genome Spain, Mutual Madrileña and Marató Foundations.

PY - 2008/4/11

Y1 - 2008/4/11

N2 - Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, ptrend = 1.7 × 10-8 and HR = 1.12, 95% CI: 1.02-1.24, ptrend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, ptrend = 5 × 10-5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

AB - Germline mutations in BRCA1 and BRCA2 confer high risks of breast cancer. However, evidence suggests that these risks are modified by other genetic or environmental factors that cluster in families. A recent genome-wide association study has shown that common alleles at single nucleotide polymorphisms (SNPs) in FGFR2 (rs2981582), TNRC9 (rs3803662), and MAP3K1 (rs889312) are associated with increased breast cancer risks in the general population. To investigate whether these loci are also associated with breast cancer risk in BRCA1 and BRCA2 mutation carriers, we genotyped these SNPs in a sample of 10,358 mutation carriers from 23 studies. The minor alleles of SNP rs2981582 and rs889312 were each associated with increased breast cancer risk in BRCA2 mutation carriers (per-allele hazard ratio [HR] = 1.32, 95% CI: 1.20-1.45, ptrend = 1.7 × 10-8 and HR = 1.12, 95% CI: 1.02-1.24, ptrend = 0.02) but not in BRCA1 carriers. rs3803662 was associated with increased breast cancer risk in both BRCA1 and BRCA2 mutation carriers (per-allele HR = 1.13, 95% CI: 1.06-1.20, ptrend = 5 × 10-5 in BRCA1 and BRCA2 combined). These loci appear to interact multiplicatively on breast cancer risk in BRCA2 mutation carriers. The differences in the effects of the FGFR2 and MAP3K1 SNPs between BRCA1 and BRCA2 carriers point to differences in the biology of BRCA1 and BRCA2 breast cancer tumors and confirm the distinct nature of breast cancer in BRCA1 mutation carriers.

UR - http://www.scopus.com/inward/record.url?scp=41649097333&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41649097333&partnerID=8YFLogxK

U2 - 10.1016/j.ajhg.2008.02.008

DO - 10.1016/j.ajhg.2008.02.008

M3 - Article

C2 - 18355772

AN - SCOPUS:41649097333

SN - 0002-9297

VL - 82

SP - 937

EP - 948

JO - American journal of human genetics

JF - American journal of human genetics

IS - 4

ER -

Common Breast Cancer-Predisposition Alleles Are Associated with Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers

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