Abstract
Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)=0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC=0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC=0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P -6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.
| Original language | English |
|---|---|
| Article number | 3416 |
| Journal | Breast Cancer Research |
| Volume | 16 |
| DOIs | |
| Publication status | Published - Dec 31 2014 |
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ASJC Scopus subject areas
- Cancer Research
- Oncology
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Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers. / Kuchenbaecker, Karoline B.; Neuhausen, Susan L.; Robson, Mark; Barrowdale, Daniel; McGuffog, Lesley; Mulligan, Anna Marie; Andrulis, Irene L.; Spurdle, Amanda B.; Schmidt, Marjanka K.; Schmutzler, Rita K.; Engel, Christoph; Wappenschmidt, Barbara; Nevanlinna, Heli; Thomassen, Mads; Southey, Melissa; Radice, Paolo; Ramus, Susan J.; Domchek, Susan M.; Nathanson, Katherine L.; Lee, Andrew; Healey, Sue; Nussbaum, Robert L.; Rebbeck, Timothy R.; Arun, Banu K.; James, Paul; Karlan, Beth Y.; Lester, Jenny; Cass, Ilana; Terry, Mary Beth; Daly, Mary B.; Goldgar, David E.; Buys, Saundra S.; Janavicius, Ramunas; Tihomirova, Laima; Tung, Nadine; Dorfling, Cecilia M.; van Rensburg, Elizabeth J.; Steele, Linda; v O Hansen, Thomas; Ejlertsen, Bent; Gerdes, Anne Marie; Nielsen, Finn C.; Dennis, Joe; Cunningham, Julie; Hart, Steven; Slager, Susan; Osorio, Ana; Benitez, Javier; Duran, Mercedes; Weitzel, Jeffrey N.; Tafur, Isaac; Hander, Mary; Peterlongo, Paolo; Manoukian, Siranoush; Peissel, Bernard; Roversi, Gaia; Scuvera, Giulietta; Bonanni, Bernardo; Mariani, Paolo; Volorio, Sara; Dolcetti, Riccardo; Varesco, Liliana; Papi, Laura; Tibiletti, Maria Grazia; Giannini, Giuseppe; Fostira, Florentia; Konstantopoulou, Irene; Garber, Judy; Hamann, Ute; Donaldson, Alan; Brewer, Carole; Foo, Claire; Evans, D. Gareth; Frost, Debra; Eccles, Diana; Douglas, Fiona; Brady, Angela; Cook, Jackie; Tischkowitz, Marc; Adlard, Julian; Barwell, Julian; Ong, Kai ren; Walker, Lisa; Izatt, Louise; Side, Lucy E.; Kennedy, M. John; Rogers, Mark T.; Porteous, Mary E.; Morrison, Patrick J.; Platte, Radka; Eeles, Ros; Davidson, Rosemarie; Hodgson, Shirley; Ellis, Steve; Godwin, Andrew K.; Rhiem, Kerstin; Meindl, Alfons; Ditsch, Nina; Arnold, Norbert; Plendl, Hansjoerg; Niederacher, Dieter; Sutter, Christian; Steinemann, Doris; Bogdanova-Markov, Nadja; Kast, Karin; Varon-Mateeva, Raymonda; Wang-Gohrke, Shan; Gehrig, Andrea; Markiefka, Birgid; Buecher, Bruno; Lefol, Cédrick; Stoppa-Lyonnet, Dominique; Rouleau, Etienne; Prieur, Fabienne; Damiola, Francesca; Barjhoux, Laure; Faivre, Laurence; Longy, Michel; Sevenet, Nicolas; Sinilnikova, Olga M.; Mazoyer, Sylvie; Bonadona, Valérie; Caux-Moncoutier, Virginie; Isaacs, Claudine; Van Maerken, Tom; Claes, Kathleen; Piedmonte, Marion; Andrews, Lesley; Hays, John; Rodriguez, Gustavo C.; Caldes, Trinidad; de la Hoya, Miguel; Khan, Sofia; Hogervorst, Frans B L; Aalfs, Cora M.; de Lange, J. L.; Meijers-Heijboer, Hanne E J; van der Hout, Annemarie H.; Wijnen, Juul T.; van Roozendaal, K. E P; Mensenkamp, Arjen R.; van den Ouweland, Ans M W; van Deurzen, Carolien H M; van der Luijt, Rob B.; Olah, Edith; Diez, Orland; Lazaro, Conxi; Blanco, Ignacio; Teulé, Alex; Menendez, Mireia; Jakubowska, Anna; Lubinski, Jan; Cybulski, Cezary; Gronwald, Jacek; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Arason, Adalgeir; Maugard, Christine; Soucy, Penny; Montagna, Marco; Agata, Simona; Teixeira, Manuel R.; Olswold, Curtis; Lindor, Noralane; Pankratz, Vernon S.; Hallberg, Emily; Wang, Xianshu; Szabo, Csilla I.; Vijai, Joseph; Jacobs, Lauren; Corines, Marina; Lincoln, Anne; Berger, Andreas; Fink-Retter, Anneliese; Singer, Christian F.; Rappaport, Christine; Kaulich, Daphne Gschwantler; Pfeiler, Georg; Tea, Muy Kheng; Phelan, Catherine M.; Mai, Phuong L.; Greene, Mark H.; Rennert, Gad; Imyanitov, Evgeny N.; Glendon, Gord; Toland, Amanda Ewart; Bojesen, Anders; Pedersen, Inge Sokilde; Jensen, Uffe Birk; Caligo, Maria A.; Friedman, Eitan; Berger, Raanan; Laitman, Yael; Rantala, Johanna; Arver, Brita; Loman, Niklas; Borg, Ake; Ehrencrona, Hans; Olopade, Olufunmilayo I.; Simard, Jacques; Easton, Douglas F.; Chenevix-Trench, Georgia; Offit, Kenneth; Couch, Fergus J.; Antoniou, Antonis C.; CIMBA, [No Value]; EMBRACE Study, Study; Breast Cancer Family, Cancer Family; GEMO Study Collaborators, Study Collaborators; HEBON, [No Value]; KConFab Investigators, Investigators.
In: Breast Cancer Research, Vol. 16, 3416, 31.12.2014.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Associations of common breast cancer susceptibility alleles with risk of breast cancer subtypes in BRCA1 and BRCA2 mutation carriers
AU - Kuchenbaecker, Karoline B.
AU - Neuhausen, Susan L.
AU - Robson, Mark
AU - Barrowdale, Daniel
AU - McGuffog, Lesley
AU - Mulligan, Anna Marie
AU - Andrulis, Irene L.
AU - Spurdle, Amanda B.
AU - Schmidt, Marjanka K.
AU - Schmutzler, Rita K.
AU - Engel, Christoph
AU - Wappenschmidt, Barbara
AU - Nevanlinna, Heli
AU - Thomassen, Mads
AU - Southey, Melissa
AU - Radice, Paolo
AU - Ramus, Susan J.
AU - Domchek, Susan M.
AU - Nathanson, Katherine L.
AU - Lee, Andrew
AU - Healey, Sue
AU - Nussbaum, Robert L.
AU - Rebbeck, Timothy R.
AU - Arun, Banu K.
AU - James, Paul
AU - Karlan, Beth Y.
AU - Lester, Jenny
AU - Cass, Ilana
AU - Terry, Mary Beth
AU - Daly, Mary B.
AU - Goldgar, David E.
AU - Buys, Saundra S.
AU - Janavicius, Ramunas
AU - Tihomirova, Laima
AU - Tung, Nadine
AU - Dorfling, Cecilia M.
AU - van Rensburg, Elizabeth J.
AU - Steele, Linda
AU - v O Hansen, Thomas
AU - Ejlertsen, Bent
AU - Gerdes, Anne Marie
AU - Nielsen, Finn C.
AU - Dennis, Joe
AU - Cunningham, Julie
AU - Hart, Steven
AU - Slager, Susan
AU - Osorio, Ana
AU - Benitez, Javier
AU - Duran, Mercedes
AU - Weitzel, Jeffrey N.
AU - Tafur, Isaac
AU - Hander, Mary
AU - Peterlongo, Paolo
AU - Manoukian, Siranoush
AU - Peissel, Bernard
AU - Roversi, Gaia
AU - Scuvera, Giulietta
AU - Bonanni, Bernardo
AU - Mariani, Paolo
AU - Volorio, Sara
AU - Dolcetti, Riccardo
AU - Varesco, Liliana
AU - Papi, Laura
AU - Tibiletti, Maria Grazia
AU - Giannini, Giuseppe
AU - Fostira, Florentia
AU - Konstantopoulou, Irene
AU - Garber, Judy
AU - Hamann, Ute
AU - Donaldson, Alan
AU - Brewer, Carole
AU - Foo, Claire
AU - Evans, D. Gareth
AU - Frost, Debra
AU - Eccles, Diana
AU - Douglas, Fiona
AU - Brady, Angela
AU - Cook, Jackie
AU - Tischkowitz, Marc
AU - Adlard, Julian
AU - Barwell, Julian
AU - Ong, Kai ren
AU - Walker, Lisa
AU - Izatt, Louise
AU - Side, Lucy E.
AU - Kennedy, M. John
AU - Rogers, Mark T.
AU - Porteous, Mary E.
AU - Morrison, Patrick J.
AU - Platte, Radka
AU - Eeles, Ros
AU - Davidson, Rosemarie
AU - Hodgson, Shirley
AU - Ellis, Steve
AU - Godwin, Andrew K.
AU - Rhiem, Kerstin
AU - Meindl, Alfons
AU - Ditsch, Nina
AU - Arnold, Norbert
AU - Plendl, Hansjoerg
AU - Niederacher, Dieter
AU - Sutter, Christian
AU - Steinemann, Doris
AU - Bogdanova-Markov, Nadja
AU - Kast, Karin
AU - Varon-Mateeva, Raymonda
AU - Wang-Gohrke, Shan
AU - Gehrig, Andrea
AU - Markiefka, Birgid
AU - Buecher, Bruno
AU - Lefol, Cédrick
AU - Stoppa-Lyonnet, Dominique
AU - Rouleau, Etienne
AU - Prieur, Fabienne
AU - Damiola, Francesca
AU - Barjhoux, Laure
AU - Faivre, Laurence
AU - Longy, Michel
AU - Sevenet, Nicolas
AU - Sinilnikova, Olga M.
AU - Mazoyer, Sylvie
AU - Bonadona, Valérie
AU - Caux-Moncoutier, Virginie
AU - Isaacs, Claudine
AU - Van Maerken, Tom
AU - Claes, Kathleen
AU - Piedmonte, Marion
AU - Andrews, Lesley
AU - Hays, John
AU - Rodriguez, Gustavo C.
AU - Caldes, Trinidad
AU - de la Hoya, Miguel
AU - Khan, Sofia
AU - Hogervorst, Frans B L
AU - Aalfs, Cora M.
AU - de Lange, J. L.
AU - Meijers-Heijboer, Hanne E J
AU - van der Hout, Annemarie H.
AU - Wijnen, Juul T.
AU - van Roozendaal, K. E P
AU - Mensenkamp, Arjen R.
AU - van den Ouweland, Ans M W
AU - van Deurzen, Carolien H M
AU - van der Luijt, Rob B.
AU - Olah, Edith
AU - Diez, Orland
AU - Lazaro, Conxi
AU - Blanco, Ignacio
AU - Teulé, Alex
AU - Menendez, Mireia
AU - Jakubowska, Anna
AU - Lubinski, Jan
AU - Cybulski, Cezary
AU - Gronwald, Jacek
AU - Jaworska-Bieniek, Katarzyna
AU - Durda, Katarzyna
AU - Arason, Adalgeir
AU - Maugard, Christine
AU - Soucy, Penny
AU - Montagna, Marco
AU - Agata, Simona
AU - Teixeira, Manuel R.
AU - Olswold, Curtis
AU - Lindor, Noralane
AU - Pankratz, Vernon S.
AU - Hallberg, Emily
AU - Wang, Xianshu
AU - Szabo, Csilla I.
AU - Vijai, Joseph
AU - Jacobs, Lauren
AU - Corines, Marina
AU - Lincoln, Anne
AU - Berger, Andreas
AU - Fink-Retter, Anneliese
AU - Singer, Christian F.
AU - Rappaport, Christine
AU - Kaulich, Daphne Gschwantler
AU - Pfeiler, Georg
AU - Tea, Muy Kheng
AU - Phelan, Catherine M.
AU - Mai, Phuong L.
AU - Greene, Mark H.
AU - Rennert, Gad
AU - Imyanitov, Evgeny N.
AU - Glendon, Gord
AU - Toland, Amanda Ewart
AU - Bojesen, Anders
AU - Pedersen, Inge Sokilde
AU - Jensen, Uffe Birk
AU - Caligo, Maria A.
AU - Friedman, Eitan
AU - Berger, Raanan
AU - Laitman, Yael
AU - Rantala, Johanna
AU - Arver, Brita
AU - Loman, Niklas
AU - Borg, Ake
AU - Ehrencrona, Hans
AU - Olopade, Olufunmilayo I.
AU - Simard, Jacques
AU - Easton, Douglas F.
AU - Chenevix-Trench, Georgia
AU - Offit, Kenneth
AU - Couch, Fergus J.
AU - Antoniou, Antonis C.
AU - CIMBA, [No Value]
AU - EMBRACE Study, Study
AU - Breast Cancer Family, Cancer Family
AU - GEMO Study Collaborators, Study Collaborators
AU - HEBON, [No Value]
AU - KConFab Investigators, Investigators
PY - 2014/12/31
Y1 - 2014/12/31
N2 - Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)=0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC=0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC=0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P -6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.
AB - Introduction: More than 70 common alleles are known to be involved in breast cancer (BC) susceptibility, and several exhibit significant heterogeneity in their associations with different BC subtypes. Although there are differences in the association patterns between BRCA1 and BRCA2 mutation carriers and the general population for several loci, no study has comprehensively evaluated the associations of all known BC susceptibility alleles with risk of BC subtypes in BRCA1 and BRCA2 carriers. Methods: We used data from 15,252 BRCA1 and 8,211 BRCA2 carriers to analyze the associations between approximately 200,000 genetic variants on the iCOGS array and risk of BC subtypes defined by estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and triple-negative- (TN) status; morphologic subtypes; histological grade; and nodal involvement. Results: The estimated BC hazard ratios (HRs) for the 74 known BC alleles in BRCA1 carriers exhibited moderate correlations with the corresponding odds ratios from the general population. However, their associations with ER-positive BC in BRCA1 carriers were more consistent with the ER-positive associations in the general population (intraclass correlation (ICC)=0.61, 95% confidence interval (CI): 0.45 to 0.74), and the same was true when considering ER-negative associations in both groups (ICC=0.59, 95% CI: 0.42 to 0.72). Similarly, there was strong correlation between the ER-positive associations for BRCA1 and BRCA2 carriers (ICC=0.67, 95% CI: 0.52 to 0.78), whereas ER-positive associations in any one of the groups were generally inconsistent with ER-negative associations in any of the others. After stratifying by ER status in mutation carriers, additional significant associations were observed. Several previously unreported variants exhibited associations at P -6 in the analyses by PR status, HER2 status, TN phenotype, morphologic subtypes, histological grade and nodal involvement. Conclusions: Differences in associations of common BC susceptibility alleles between BRCA1 and BRCA2 carriers and the general population are explained to a large extent by differences in the prevalence of ER-positive and ER-negative tumors. Estimates of the risks associated with these variants based on population-based studies are likely to be applicable to mutation carriers after taking ER status into account, which has implications for risk prediction.
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U2 - 10.1186/s13058-014-0492-9
DO - 10.1186/s13058-014-0492-9
M3 - Article
VL - 16
JO - Breast Cancer Research
JF - Breast Cancer Research
SN - 1465-5411
M1 - 3416
ER -