Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

Couch, F. J.; Wang, X.; McGuffog, L.; Lee, A.; Olswold, C.; Kuchenbaecker, K. B.; Soucy, P.; Fredericksen, Z.; Barrowdale, D.; Dennis, J.; Gaudet, M. M.; Dicks, E.; Kosel, M.; Healey, S.; Sinilnikova, O. M.; Bacot, F.; Vincent, D.; Hogervorst, F. B.; Peock, S.; Stoppa-Lyonnet, D.; Jakubowska, A.; Investigators, kConFab; Radice, P.; Schmutzler, R. K.; SWE-BRCA,; Domchek, S. M.; Piedmonte, M.; Singer, C. F.; Friedman, E.; Thomassen, M.; Network, Ontario Cancer Genetics; Hansen, T. V.; Neuhausen, S. L.; Szabo, C. I.; Blanco, I.; Greene, M. H.; Karlan, B. Y.; Garber, J.; Phelan, C. M.; Weitzel, J. N.; Montagna, M.; Olah, E.; Andrulis, I. L.; Godwin, A. K.; Yannoukakos, D.; Goldgar, D. E.; Caldes, T.; Nevanlinna, H.; Osorio, A.; Terry, M. B.; Daly, M. B.; van Rensburg, E. J.; Hamann, U.; Ramus, S. J.; Toland, A. E.; Caligo, M. A.; Olopade, O. I.; Tung, N.; Claes, K.; Beattie, M. S.; Southey, M. C.; Imyanitov, E. N.; Tischkowitz, M.; Janavicius, R.; John, E. M.; Kwong, A.; Diez, O.; Balmaña, J.; Barkardottir, R. B.; Arun, B. K.; Rennert, G.; Teo, S. H.; Ganz, P. A.; Campbell, I.; van der Hout, A. H.; van Deurzen, C. H.; Seynaeve, C.; Gómez Garcia, E. B.; van Leeuwen, F. E.; Meijers-Heijboer, H. E.; Gille, J. J.; Ausems, M. G.; Blok, M. J.; Ligtenberg, M. J.; Rookus, M. A.; Devilee, P.; Verhoef, S.; van Os, T. A.; Wijnen, J. T.; HEBON,; EMBRACE,; Frost, D.; Ellis, S.; Fineberg, E.; Platte, R.; Evans, D. G.; Izatt, L.; Eeles, R. A.; Adlard, J.; Eccles, D. M.; Cook, J.; Brewer, C.; Douglas, F.; Hodgson, S.; Morrison, P. J.; Side, L. E.; Donaldson, A.; Houghton, C.; Rogers, M. T.; Dorkins, H.; Eason, J.; Gregory, H.; McCann, E.; Murray, A.; Calender, A.; Hardouin, A.; Berthet, P.; Delnatte, C.; Nogues, C.; Lasset, C.; Houdayer, C.; Leroux, D.; Rouleau, E.; Prieur, F.; Damiola, F.; Sobol, H.; Coupier, I.; Venat-Bouvet, L.; Castera, L.; Gauthier-Villars, M.; Léoné, M.; Pujol, P.; Mazoyer, S.; Bignon, Y. J.; Collaborators, GEMO Study; Złowocka-Perłowska, E.; Gronwald, J.; Lubinski, J.; Durda, K.; Jaworska, K.; Huzarski, T.; Spurdle, A. B.; Viel, A.; Peissel, B.; Bonanni, B.; Melloni, G.; Ottini, L.; Papi, L.; Varesco, L.; Tibiletti, M. G.; Peterlongo, P.; Volorio, S.; Manoukian, S.; Pensotti, V.; Arnold, N.; Engel, C.; Deissler, H.; Gadzicki, D.; Gehrig, A.; Kast, K.; Rhiem, K.; Meindl, A.; Niederacher, D.; Ditsch, N.; Plendl, H.; Preisler-Adams, S.; Engert, S.; Sutter, C.; Varon-Mateeva, R.; Wappenschmidt, B.; Weber, B. H.; Arver, B.; Stenmark-Askmalm, M.; Loman, N.; Rosenquist, R.; Einbeigi, Z.; Nathanson, K. L.; Rebbeck, T. R.; Blank, S. V.; Cohn, D. E.; Rodriguez, G. C.; Small, L.; Friedlander, M.; Bae-Jump, V. L.; Fink-Retter, A.; Rappaport, C.; Gschwantler-Kaulich, D.; Pfeiler, G.; Tea, M. K.; Lindor, N. M.; Kaufman, B.; Shimon Paluch, S.; Laitman, Y.; Skytte, A. B.; Gerdes, A. M.; Pedersen, I. S.; Moeller, S. T.; Kruse, T. A.; Jensen, U. B.; Vijai, J.; Sarrel, K.; Robson, M.; Kauff, N.; Mulligan, A. M.; Glendon, G.; Ozcelik, H.; Ejlertsen, B.; Nielsen, F. C.; Jønson, L.; Andersen, M. K.; Ding, Y. C.; Steele, L.; Foretova, L.; Teulé, A.; Lazaro, C.; Brunet, J.; Pujana, M. A.; Mai, P. L.; Loud, J. T.; Walsh, C.; Lester, J.; Orsulic, S.; Narod, S. A.; Herzog, J.; Sand, S. R.; Tognazzo, S.; Agata, S.; Vaszko, T.; Weaver, J.; Stavropoulou, A. V.; Buys, S. S.; Romero, A.; de la Hoya, M.; Aittomäki, K.; Muranen, T. A.; Duran, M.; Chung, W. K.; Lasa, A.; Dorfling, C. M.; Miron, A.; BCFR,; Benitez, J.; Senter, L.; Huo, D.; Chan, S. B.; Sokolenko, A. P.; Chiquette, J.; Tihomirova, L.; Friebel, T. M.; Agnarsson, B. A.; Lu, K. H.; Lejbkowicz, F.; James, P. A.; Hall, P.; Dunning, A. M.; Tessier, D.; Cunningham, J.; Slager, S. L.; Wang, C.; Hart, S.; Stevens, K.; Simard, J.; Pastinen, T.; Pankratz, V. S.; Offit, K.; Easton, D. F.; Chenevix-Trench, G.; Antoniou, A. C.; CIMBA,

Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk..pdf (2.88 MB)

Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

journal contribution

posted on 2016-04-14, 09:17 authored by F. J. Couch, X. Wang, L. McGuffog, A. Lee, C. Olswold, K. B. Kuchenbaecker, P. Soucy, Z. Fredericksen, D. Barrowdale, J. Dennis, M. M. Gaudet, E. Dicks, M. Kosel, S. Healey, O. M. Sinilnikova, F. Bacot, D. Vincent, F. B. Hogervorst, S. Peock, D. Stoppa-Lyonnet, A. Jakubowska, kConFab Investigators, P. Radice, R. K. Schmutzler, SWE-BRCA, S. M. Domchek, M. Piedmonte, C. F. Singer, E. Friedman, M. Thomassen, Ontario Cancer Genetics Network, T. V. Hansen, S. L. Neuhausen, C. I. Szabo, I. Blanco, M. H. Greene, B. Y. Karlan, J. Garber, C. M. Phelan, J. N. Weitzel, M. Montagna, E. Olah, I. L. Andrulis, A. K. Godwin, D. Yannoukakos, D. E. Goldgar, T. Caldes, H. Nevanlinna, A. Osorio, M. B. Terry, M. B. Daly, E. J. van Rensburg, U. Hamann, S. J. Ramus, A. E. Toland, M. A. Caligo, O. I. Olopade, N. Tung, K. Claes, M. S. Beattie, M. C. Southey, E. N. Imyanitov, M. Tischkowitz, R. Janavicius, E. M. John, A. Kwong, O. Diez, J. Balmaña, R. B. Barkardottir, B. K. Arun, G. Rennert, S. H. Teo, P. A. Ganz, I. Campbell, A. H. van der Hout, C. H. van Deurzen, C. Seynaeve, E. B. Gómez Garcia, F. E. van Leeuwen, H. E. Meijers-Heijboer, J. J. Gille, M. G. Ausems, M. J. Blok, M. J. Ligtenberg, M. A. Rookus, P. Devilee, S. Verhoef, T. A. van Os, J. T. Wijnen, HEBON, EMBRACE, D. Frost, S. Ellis, E. Fineberg, R. Platte, D. G. Evans, L. Izatt, R. A. Eeles, J. Adlard, D. M. Eccles, J. Cook, C. Brewer, F. Douglas, S. Hodgson, P. J. Morrison, L. E. Side, A. Donaldson, C. Houghton, M. T. Rogers, H. Dorkins, J. Eason, H. Gregory, E. McCann, A. Murray, A. Calender, A. Hardouin, P. Berthet, C. Delnatte, C. Nogues, C. Lasset, C. Houdayer, D. Leroux, E. Rouleau, F. Prieur, F. Damiola, H. Sobol, I. Coupier, L. Venat-Bouvet, L. Castera, M. Gauthier-Villars, M. Léoné, P. Pujol, S. Mazoyer, Y. J. Bignon, GEMO Study Collaborators, E. Złowocka-Perłowska, J. Gronwald, J. Lubinski, K. Durda, K. Jaworska, T. Huzarski, A. B. Spurdle, A. Viel, B. Peissel, B. Bonanni, G. Melloni, L. Ottini, L. Papi, L. Varesco, M. G. Tibiletti, P. Peterlongo, S. Volorio, S. Manoukian, V. Pensotti, N. Arnold, C. Engel, H. Deissler, D. Gadzicki, A. Gehrig, K. Kast, K. Rhiem, A. Meindl, D. Niederacher, N. Ditsch, H. Plendl, S. Preisler-Adams, S. Engert, C. Sutter, R. Varon-Mateeva, B. Wappenschmidt, B. H. Weber, B. Arver, M. Stenmark-Askmalm, N. Loman, R. Rosenquist, Z. Einbeigi, K. L. Nathanson, T. R. Rebbeck, S. V. Blank, D. E. Cohn, G. C. Rodriguez, L. Small, M. Friedlander, V. L. Bae-Jump, A. Fink-Retter, C. Rappaport, D. Gschwantler-Kaulich, G. Pfeiler, M. K. Tea, N. M. Lindor, B. Kaufman, S. Shimon Paluch, Y. Laitman, A. B. Skytte, A. M. Gerdes, I. S. Pedersen, S. T. Moeller, T. A. Kruse, U. B. Jensen, J. Vijai, K. Sarrel, M. Robson, N. Kauff, A. M. Mulligan, G. Glendon, H. Ozcelik, B. Ejlertsen, F. C. Nielsen, L. Jønson, M. K. Andersen, Y. C. Ding, L. Steele, L. Foretova, A. Teulé, C. Lazaro, J. Brunet, M. A. Pujana, P. L. Mai, J. T. Loud, C. Walsh, J. Lester, S. Orsulic, S. A. Narod, J. Herzog, S. R. Sand, S. Tognazzo, S. Agata, T. Vaszko, J. Weaver, A. V. Stavropoulou, S. S. Buys, A. Romero, M. de la Hoya, K. Aittomäki, T. A. Muranen, M. Duran, W. K. Chung, A. Lasa, C. M. Dorfling, A. Miron, BCFR, J. Benitez, L. Senter, D. Huo, S. B. Chan, A. P. Sokolenko, J. Chiquette, L. Tihomirova, T. M. Friebel, B. A. Agnarsson, K. H. Lu, F. Lejbkowicz, P. A. James, P. Hall, A. M. Dunning, D. Tessier, J. Cunningham, S. L. Slager, C. Wang, S. Hart, K. Stevens, J. Simard, T. Pastinen, V. S. Pankratz, K. Offit, D. F. Easton, G. Chenevix-Trench, A. C. Antoniou, CIMBA

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

History

Citation

PLoS Genetics, 2013, 9 (3), e1003212

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

Version

VoR (Version of Record)

Published in

PLoS Genetics

Publisher

Public Library of Science

issn

1553-7390

eissn

1553-7404

Acceptance date

2012-11-14

Copyright date

2013

Available date

2016-04-14

Publisher DOI

https://doi.org/10.1371/journal.pgen.1003212

Publisher version

http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1003212

Language

en

Administrator link

https://leicester.figshare.com/account/articles/10162478

Usage metrics

Keywords

BRCA1 Protein BRCA2 Protein Breast Neoplasms Female Genetic Predisposition to Disease Genome-Wide Association Study Genotype Heterozygote Humans Middle Aged Mutation Ovarian Neoplasms Polymorphism, Single Nucleotide Prognosis Risk Factors

Licence

Exports

RefWorks

BibTeX

Ref. manager

Endnote

DataCite

NLM

DC

Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

History

Citation

Author affiliation

Version

Published in

Publisher

issn

eissn

Acceptance date

Copyright date

Available date

Publisher DOI

Publisher version

Language

Administrator link

Usage metrics

Categories

Keywords

Licence

Exports