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- PMID: 23544013
- UKPMCID: 23544013
- DOI: 10.1371/journal.pgen.1003212
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Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.
Couch, Fergus J; Wang, Xianshu; McGuffog, Lesley; Lee, Andrew; Olswold, Curtis; Kuchenbaecker, Karoline B; Soucy, Penny; Fredericksen, Zachary; Barrowdale, Daniel; Dennis, Joe; Gaudet, Mia M; Dicks, Ed; Kosel, Matthew; Healey, Sue; Sinilnikova, Olga M; Lee, Adam; Bacot, François; Vincent, Daniel; Hogervorst, Frans B L; Peock, Susan; Stoppa-Lyonnet, Dominique; Jakubowska, Anna; ; Radice, Paolo; Schmutzler, Rita Katharina; ; Domchek, Susan M; Piedmonte, Marion; Singer, Christian F; Friedman, Eitan; Thomassen, Mads; ; Hansen, Thomas V O; Neuhausen, Susan L; Szabo, Csilla I; Blanco, Ignacio; Greene, Mark H; Karlan, Beth Y; Garber, Judy; Phelan, Catherine M; Weitzel, Jeffrey N; Montagna, Marco; Olah, Edith; Andrulis, Irene L; Godwin, Andrew K; Yannoukakos, Drakoulis; Goldgar, David E; Caldes, Trinidad; Nevanlinna, Heli; Osorio, Ana; Terry, Mary Beth; Daly, Mary B; van Rensburg, Elizabeth J; Hamann, Ute; Ramus, Susan J; Toland, Amanda Ewart; Caligo, Maria A; Olopade, Olufunmilayo I; Tung, Nadine; Claes, Kathleen; Beattie, Mary S; Southey, Melissa C; Imyanitov, Evgeny N; Tischkowitz, Marc; Janavicius, Ramunas; John, Esther M; Kwong, Ava; Diez, Orland; Balmaña, Judith; Barkardottir, Rosa B; Arun, Banu K; Rennert, Gad; Teo, Soo-Hwang; Ganz, Patricia A; Campbell, Ian; van der Hout, Annemarie H; van Deurzen, Carolien H M; Seynaeve, Caroline; Gómez Garcia, Encarna B; van Leeuwen, Flora E; Meijers-Heijboer, Hanne E J; Gille, Johannes J P; Ausems, Margreet G E M; Blok, Marinus J; Ligtenberg, Marjolijn J L; Rookus, Matti A; Devilee, Peter; Verhoef, Senno; van Os, Theo A M; Wijnen, Juul T; ; ; Frost, Debra; Ellis, Steve; Fineberg, Elena; Platte, Radka; Evans, D Gareth; Izatt, Louise; Eeles, Rosalind A; Adlard, Julian; Eccles, Diana M; Cook, Jackie; Brewer, Carole; Douglas, Fiona; Hodgson, Shirley; Morrison, Patrick J; Side, Lucy E; Donaldson, Alan; Houghton, Catherine; Rogers, Mark T; Dorkins, Huw; Eason, Jacqueline; Gregory, Helen; McCann, Emma; Murray, Alex; Calender, Alain; Hardouin, Agnès; Berthet, Pascaline; Delnatte, Capucine; Nogues, Catherine; Lasset, Christine; Houdayer, Claude; Leroux, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Sobol, Hagay; Coupier, Isabelle; Venat-Bouvet, Laurence; Castera, Laurent; Gauthier-Villars, Marion; Léoné, Mélanie; Pujol, Pascal; Mazoyer, Sylvie; Bignon, Yves-Jean; ; Złowocka-Perłowska, Elżbieta; Gronwald, Jacek; Lubinski, Jan; Durda, Katarzyna; Jaworska, Katarzyna; Huzarski, Tomasz; Spurdle, Amanda B; Viel, Alessandra; Peissel, Bernard; Bonanni, Bernardo; Melloni, Giulia; Ottini, Laura; Papi, Laura; Varesco, Liliana; Tibiletti, Maria Grazia; Peterlongo, Paolo; Volorio, Sara; Manoukian, Siranoush; Pensotti, Valeria; Arnold, Norbert; Engel, Christoph; Deissler, Helmut; Gadzicki, Dorothea; Gehrig, Andrea; Kast, Karin; Rhiem, Kerstin; Meindl, Alfons; Niederacher, Dieter; Ditsch, Nina; Plendl, Hansjoerg; Preisler-Adams, Sabine; Engert, Stefanie; Sutter, Christian; Varon-Mateeva, Raymonda; Wappenschmidt, Barbara; Weber, Bernhard H F; Arver, Brita; Stenmark-Askmalm, Marie; Loman, Niklas; Rosenquist, Richard; Einbeigi, Zakaria; Nathanson, Katherine L; Rebbeck, Timothy R; Blank, Stephanie V; Cohn, David E; Rodriguez, Gustavo C; Small, Laurie; Friedlander, Michael; Bae-Jump, Victoria L; Fink-Retter, Anneliese; Rappaport, Christine; Gschwantler-Kaulich, Daphne; Pfeiler, Georg; Tea, Muy-Kheng; Lindor, Noralane M; Kaufman, Bella; Shimon Paluch, Shani; Laitman, Yael; Skytte, Anne-Bine; Gerdes, Anne-Marie; Pedersen, Inge Sokilde; Moeller, Sanne Traasdahl; Kruse, Torben A; Jensen, Uffe Birk; Vijai, Joseph; Sarrel, Kara; Robson, Mark; Kauff, Noah; Mulligan, Anna Marie; Glendon, Gord; Ozcelik, Hilmi; Ejlertsen, Bent; Nielsen, Finn C; Jønson, Lars; Andersen, Mette K; Ding, Yuan Chun; Steele, Linda; Foretova, Lenka; Teulé, Alex; Lazaro, Conxi; Brunet, Joan; Pujana, Miquel Angel; Mai, Phuong L; Loud, Jennifer T; Walsh, Christine; Lester, Jenny; Orsulic, Sandra; Narod, Steven A; Herzog, Josef; Sand, Sharon R; Tognazzo, Silvia; Agata, Simona; Vaszko, Tibor; Weaver, Joellen; Stavropoulou, Alexandra V; Buys, Saundra S; Romero, Atocha; de la Hoya, Miguel; Aittomäki, Kristiina; Muranen, Taru A; Duran, Mercedes; Chung, Wendy K; Lasa, Adriana; Dorfling, Cecilia M; Miron, Alexander; ; Benitez, Javier; Senter, Leigha; Huo, Dezheng; Chan, Salina B; Sokolenko, Anna P; Chiquette, Jocelyne; Tihomirova, Laima; Friebel, Tara M; Agnarsson, Bjarni A; Lu, Karen H; Lejbkowicz, Flavio; James, Paul A; Hall, Per; Dunning, Alison M; Tessier, Daniel; Cunningham, Julie; Slager, Susan L; Wang, Chen; Hart, Steven; Stevens, Kristen; Simard, Jacques; Pastinen, Tomi; Pankratz, Vernon S; Offit, Kenneth; Easton, Douglas F; Chenevix-Trench, Georgia; Antoniou, Antonis C;
PLoS genetics. 2013;9(3):e1003212.
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Full-text held externally
- PMID: 23544013
- UKPMCID: 23544013
- DOI: 10.1371/journal.pgen.1003212
Abstract
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.
Bibliographic metadata
- Couch, Fergus J
- Wang, Xianshu
- McGuffog, Lesley
- Lee, Andrew
- Olswold, Curtis
- Kuchenbaecker, Karoline B
- Soucy, Penny
- Fredericksen, Zachary
- Barrowdale, Daniel
- Dennis, Joe
- Gaudet, Mia M
- Dicks, Ed
- Kosel, Matthew
- Healey, Sue
- Sinilnikova, Olga M
- Lee, Adam
- Bacot, François
- Vincent, Daniel
- Hogervorst, Frans B L
- Peock, Susan
- Stoppa-Lyonnet, Dominique
- Jakubowska, Anna
- Radice, Paolo
- Schmutzler, Rita Katharina
- Domchek, Susan M
- Piedmonte, Marion
- Singer, Christian F
- Friedman, Eitan
- Thomassen, Mads
- Hansen, Thomas V O
- Neuhausen, Susan L
- Szabo, Csilla I
- Blanco, Ignacio
- Greene, Mark H
- Karlan, Beth Y
- Garber, Judy
- Phelan, Catherine M
- Weitzel, Jeffrey N
- Montagna, Marco
- Olah, Edith
- Andrulis, Irene L
- Godwin, Andrew K
- Yannoukakos, Drakoulis
- Goldgar, David E
- Caldes, Trinidad
- Nevanlinna, Heli
- Osorio, Ana
- Terry, Mary Beth
- Daly, Mary B
- van Rensburg, Elizabeth J
- Hamann, Ute
- Ramus, Susan J
- Toland, Amanda Ewart
- Caligo, Maria A
- Olopade, Olufunmilayo I
- Tung, Nadine
- Claes, Kathleen
- Beattie, Mary S
- Southey, Melissa C
- Imyanitov, Evgeny N
- Tischkowitz, Marc
- Janavicius, Ramunas
- John, Esther M
- Kwong, Ava
- Diez, Orland
- Balmaña, Judith
- Barkardottir, Rosa B
- Arun, Banu K
- Rennert, Gad
- Teo, Soo-Hwang
- Ganz, Patricia A
- Campbell, Ian
- van der Hout, Annemarie H
- van Deurzen, Carolien H M
- Seynaeve, Caroline
- Gómez Garcia, Encarna B
- van Leeuwen, Flora E
- Meijers-Heijboer, Hanne E J
- Gille, Johannes J P
- Ausems, Margreet G E M
- Blok, Marinus J
- Ligtenberg, Marjolijn J L
- Rookus, Matti A
- Devilee, Peter
- Verhoef, Senno
- van Os, Theo A M
- Wijnen, Juul T
- Frost, Debra
- Ellis, Steve
- Fineberg, Elena
- Platte, Radka
- Evans, D Gareth
- Izatt, Louise
- Eeles, Rosalind A
- Adlard, Julian
- Eccles, Diana M
- Cook, Jackie
- Brewer, Carole
- Douglas, Fiona
- Hodgson, Shirley
- Morrison, Patrick J
- Side, Lucy E
- Donaldson, Alan
- Houghton, Catherine
- Rogers, Mark T
- Dorkins, Huw
- Eason, Jacqueline
- Gregory, Helen
- McCann, Emma
- Murray, Alex
- Calender, Alain
- Hardouin, Agnès
- Berthet, Pascaline
- Delnatte, Capucine
- Nogues, Catherine
- Lasset, Christine
- Houdayer, Claude
- Leroux, Dominique
- Rouleau, Etienne
- Prieur, Fabienne
- Damiola, Francesca
- Sobol, Hagay
- Coupier, Isabelle
- Venat-Bouvet, Laurence
- Castera, Laurent
- Gauthier-Villars, Marion
- Léoné, Mélanie
- Pujol, Pascal
- Mazoyer, Sylvie
- Bignon, Yves-Jean
- Złowocka-Perłowska, Elżbieta
- Gronwald, Jacek
- Lubinski, Jan
- Durda, Katarzyna
- Jaworska, Katarzyna
- Huzarski, Tomasz
- Spurdle, Amanda B
- Viel, Alessandra
- Peissel, Bernard
- Bonanni, Bernardo
- Melloni, Giulia
- Ottini, Laura
- Papi, Laura
- Varesco, Liliana
- Tibiletti, Maria Grazia
- Peterlongo, Paolo
- Volorio, Sara
- Manoukian, Siranoush
- Pensotti, Valeria
- Arnold, Norbert
- Engel, Christoph
- Deissler, Helmut
- Gadzicki, Dorothea
- Gehrig, Andrea
- Kast, Karin
- Rhiem, Kerstin
- Meindl, Alfons
- Niederacher, Dieter
- Ditsch, Nina
- Plendl, Hansjoerg
- Preisler-Adams, Sabine
- Engert, Stefanie
- Sutter, Christian
- Varon-Mateeva, Raymonda
- Wappenschmidt, Barbara
- Weber, Bernhard H F
- Arver, Brita
- Stenmark-Askmalm, Marie
- Loman, Niklas
- Rosenquist, Richard
- Einbeigi, Zakaria
- Nathanson, Katherine L
- Rebbeck, Timothy R
- Blank, Stephanie V
- Cohn, David E
- Rodriguez, Gustavo C
- Small, Laurie
- Friedlander, Michael
- Bae-Jump, Victoria L
- Fink-Retter, Anneliese
- Rappaport, Christine
- Gschwantler-Kaulich, Daphne
- Pfeiler, Georg
- Tea, Muy-Kheng
- Lindor, Noralane M
- Kaufman, Bella
- Shimon Paluch, Shani
- Laitman, Yael
- Skytte, Anne-Bine
- Gerdes, Anne-Marie
- Pedersen, Inge Sokilde
- Moeller, Sanne Traasdahl
- Kruse, Torben A
- Jensen, Uffe Birk
- Vijai, Joseph
- Sarrel, Kara
- Robson, Mark
- Kauff, Noah
- Mulligan, Anna Marie
- Glendon, Gord
- Ozcelik, Hilmi
- Ejlertsen, Bent
- Nielsen, Finn C
- Jønson, Lars
- Andersen, Mette K
- Ding, Yuan Chun
- Steele, Linda
- Foretova, Lenka
- Teulé, Alex
- Lazaro, Conxi
- Brunet, Joan
- Pujana, Miquel Angel
- Mai, Phuong L
- Loud, Jennifer T
- Walsh, Christine
- Lester, Jenny
- Orsulic, Sandra
- Narod, Steven A
- Herzog, Josef
- Sand, Sharon R
- Tognazzo, Silvia
- Agata, Simona
- Vaszko, Tibor
- Weaver, Joellen
- Stavropoulou, Alexandra V
- Buys, Saundra S
- Romero, Atocha
- de la Hoya, Miguel
- Aittomäki, Kristiina
- Muranen, Taru A
- Duran, Mercedes
- Chung, Wendy K
- Lasa, Adriana
- Dorfling, Cecilia M
- Miron, Alexander
- Benitez, Javier
- Senter, Leigha
- Huo, Dezheng
- Chan, Salina B
- Sokolenko, Anna P
- Chiquette, Jocelyne
- Tihomirova, Laima
- Friebel, Tara M
- Agnarsson, Bjarni A
- Lu, Karen H
- Lejbkowicz, Flavio
- James, Paul A
- Hall, Per
- Dunning, Alison M
- Tessier, Daniel
- Cunningham, Julie
- Slager, Susan L
- Wang, Chen
- Hart, Steven
- Stevens, Kristen
- Simard, Jacques
- Pastinen, Tomi
- Pankratz, Vernon S
- Offit, Kenneth
- Easton, Douglas F
- Chenevix-Trench, Georgia
- Antoniou, Antonis C
- 5U01CA113916, NCI NIH HHS, United States
- C12292/A11174, Cancer Research UK, United Kingdom
- C1287/A10118, Cancer Research UK, United Kingdom
- C1287/A11990, Cancer Research UK, United Kingdom
- C5047/A8385, Cancer Research UK, United Kingdom
- CA 101165, NCI NIH HHS, United States
- CA 27469, NCI NIH HHS, United States
- CA 37517, NCI NIH HHS, United States
- CA-06-503, NCI NIH HHS, United States
- CA116201, NCI NIH HHS, United States
- CA128978, NCI NIH HHS, United States
- N02-CP-11019-50, NCI NIH HHS, United States
- N02-CP-65504, NCI NIH HHS, United States
- P01 CA16094, NCI NIH HHS, United States
- P30 CA033752, NCI NIH HHS, United States
- P30 CA042014, NCI NIH HHS, United States
- P30 CA13696, NCI NIH HHS, United States
- P30 ES009089, NIEHS NIH HHS, United States
- P50 CA116201, NCI NIH HHS, United States
- R01 CA128978, NCI NIH HHS, United States
- R01 CA22435, NCI NIH HHS, United States
- R01-CA083855, NCI NIH HHS, United States
- R01-CA102776, NCI NIH HHS, United States
- R01CA140323, NCI NIH HHS, United States
- R01CA74415, NCI NIH HHS, United States
- R25 CA092049, NCI NIH HHS, United States
- RC4 CA153828, NCI NIH HHS, United States
- RC4A153828, CCR NIH HHS, United States
- U01 CA69398, NCI NIH HHS, United States
- U01 CA69417, NCI NIH HHS, United States
- U01 CA69446, NCI NIH HHS, United States
- U01 CA69467, NCI NIH HHS, United States
- U01 CA69631, NCI NIH HHS, United States
- U01 CA69638, NCI NIH HHS, United States
- UL1 RR025764, NCRR NIH HHS, United States