Abstract
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10-8) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10-4] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10-9) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10-69). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
Original language | English (US) |
---|---|
Pages (from-to) | 1012-1019 |
Number of pages | 8 |
Journal | Carcinogenesis |
Volume | 35 |
Issue number | 5 |
DOIs | |
State | Published - Apr 2014 |
ASJC Scopus subject areas
- Cancer Research
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Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer. / Purrington, Kristen S.; Slager, Susan; Eccles, Diana; Yannoukakos, Drakoulis; Fasching, Peter A.; Miron, Penelope; Carpenter, Jane; Chang-claude, Jenny; Martin, Nicholas G.; Montgomery, Grant W.; Kristensen, Vessela; Anton-Culver, Hoda; Goodfellow, Paul; Tapper, William J.; Rafiq, Sajjad; Gerty, Susan M.; Durcan, Lorraine; Konstantopoulou, Irene; Fostira, Florentia; Vratimos, Athanassios; Apostolou, Paraskevi; Konstanta, Irene; Kotoula, Vassiliki; Lakis, Sotiris; Dimopoulos, Meletios A.; Skarlos, Dimosthenis; Pectasides, Dimitrios; Fountzilas, George; Beckmann, Matthias W.; Hein, Alexander; Ruebner, Matthias; Ekici, Arif B.; Hartmann, Arndt; Schulz-wendtland, Ruediger; Renner, Stefan P.; Janni, Wolfgang; Rack, Brigitte; Scholz, Christoph; Neugebauer, Julia; Andergassen, Ulrich; Lux, Michael P.; Haeberle, Lothar; Clarke, Christine; Pathmanathan, Nirmala; Rudolph, Anja; Flesch-janys, Dieter; Nickels, Stefan; Olson, Janet E.; Ingle, James N.; Olswold, Curtis; Slettedahl, Seth; Eckel-passow, Jeanette E.; Anderson, S. Keith; Visscher, Daniel W.; Cafourek, Victoria L.; Sicotte, Hugues; Prodduturi, Naresh; Weiderpass, Elisabete; Bernstein, Leslie; Ziogas, Argyrios; Ivanovich, Jennifer; Giles, Graham G.; Baglietto, Laura; Southey, Melissa; Kosma, Veli Matti; Fischer, Hans Peter; Reed, Malcom W.R.; Cross, Simon S.; Deming-halverson, Sandra; Shrubsole, Martha; Cai, Qiuyin; Shu, Xiao Ou; Daly, Mary; Weaver, Jo Ellen; Ross, Eric; Klemp, Jennifer; Sharma, Priyanka; Torres, Diana; Rüdiger, Thomas; Wölfing, Heidrun; Ulmer, Hans Ulrich; Försti, Asta; Khoury, Thaer; Kumar, Shicha; Pilarski, Robert; Shapiro, Charles L.; Greco, Dario; Heikkilä, Päivi; Aittomäki, Kristiina; Blomqvist, Carl; Irwanto, Astrid; Liu, Jianjun; Pankratz, Vernon Shane; Wang, Xianshu; Severi, Gianluca; Mannermaa, Arto; Easton, Douglas; Hall, Per; Brauch, Hiltrud; Cox, Angela; Zheng, Wei; Godwin, Andrew K.; Hamann, Ute; Ambrosone, Christine; Toland, Amanda Ewart; Nevanlinna, Heli; Vachon, Celine M.; Couch, Fergus J.
In: Carcinogenesis, Vol. 35, No. 5, 04.2014, p. 1012-1019.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer
AU - Purrington, Kristen S.
AU - Slager, Susan
AU - Eccles, Diana
AU - Yannoukakos, Drakoulis
AU - Fasching, Peter A.
AU - Miron, Penelope
AU - Carpenter, Jane
AU - Chang-claude, Jenny
AU - Martin, Nicholas G.
AU - Montgomery, Grant W.
AU - Kristensen, Vessela
AU - Anton-Culver, Hoda
AU - Goodfellow, Paul
AU - Tapper, William J.
AU - Rafiq, Sajjad
AU - Gerty, Susan M.
AU - Durcan, Lorraine
AU - Konstantopoulou, Irene
AU - Fostira, Florentia
AU - Vratimos, Athanassios
AU - Apostolou, Paraskevi
AU - Konstanta, Irene
AU - Kotoula, Vassiliki
AU - Lakis, Sotiris
AU - Dimopoulos, Meletios A.
AU - Skarlos, Dimosthenis
AU - Pectasides, Dimitrios
AU - Fountzilas, George
AU - Beckmann, Matthias W.
AU - Hein, Alexander
AU - Ruebner, Matthias
AU - Ekici, Arif B.
AU - Hartmann, Arndt
AU - Schulz-wendtland, Ruediger
AU - Renner, Stefan P.
AU - Janni, Wolfgang
AU - Rack, Brigitte
AU - Scholz, Christoph
AU - Neugebauer, Julia
AU - Andergassen, Ulrich
AU - Lux, Michael P.
AU - Haeberle, Lothar
AU - Clarke, Christine
AU - Pathmanathan, Nirmala
AU - Rudolph, Anja
AU - Flesch-janys, Dieter
AU - Nickels, Stefan
AU - Olson, Janet E.
AU - Ingle, James N.
AU - Olswold, Curtis
AU - Slettedahl, Seth
AU - Eckel-passow, Jeanette E.
AU - Anderson, S. Keith
AU - Visscher, Daniel W.
AU - Cafourek, Victoria L.
AU - Sicotte, Hugues
AU - Prodduturi, Naresh
AU - Weiderpass, Elisabete
AU - Bernstein, Leslie
AU - Ziogas, Argyrios
AU - Ivanovich, Jennifer
AU - Giles, Graham G.
AU - Baglietto, Laura
AU - Southey, Melissa
AU - Kosma, Veli Matti
AU - Fischer, Hans Peter
AU - Reed, Malcom W.R.
AU - Cross, Simon S.
AU - Deming-halverson, Sandra
AU - Shrubsole, Martha
AU - Cai, Qiuyin
AU - Shu, Xiao Ou
AU - Daly, Mary
AU - Weaver, Jo Ellen
AU - Ross, Eric
AU - Klemp, Jennifer
AU - Sharma, Priyanka
AU - Torres, Diana
AU - Rüdiger, Thomas
AU - Wölfing, Heidrun
AU - Ulmer, Hans Ulrich
AU - Försti, Asta
AU - Khoury, Thaer
AU - Kumar, Shicha
AU - Pilarski, Robert
AU - Shapiro, Charles L.
AU - Greco, Dario
AU - Heikkilä, Päivi
AU - Aittomäki, Kristiina
AU - Blomqvist, Carl
AU - Irwanto, Astrid
AU - Liu, Jianjun
AU - Pankratz, Vernon Shane
AU - Wang, Xianshu
AU - Severi, Gianluca
AU - Mannermaa, Arto
AU - Easton, Douglas
AU - Hall, Per
AU - Brauch, Hiltrud
AU - Cox, Angela
AU - Zheng, Wei
AU - Godwin, Andrew K.
AU - Hamann, Ute
AU - Ambrosone, Christine
AU - Toland, Amanda Ewart
AU - Nevanlinna, Heli
AU - Vachon, Celine M.
AU - Couch, Fergus J.
N1 - Funding Information: Insurance (IPA), Bochum, as well as the Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn, Germany; OSU studies were supported by the OSU Comprehensive Cancer Center and the Stefanie Spielman Fund; SBCS was supported by Yorkshire Cancer Research Programme (S305PA); SKKDKFZS is supported by the DKFZ. The Demokritos has been co-financed by the European Union (European Social Fund) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework - Research Funding Program: Thales. Investing in knowledge society through the European Social Fund; The University of Kansas Cancer Center’s (P30 CA168524) Biospecimen Repository Core Facility. A.K.G. was funded by National Institutes of Health (5U01CA113916 and R01CA14032), a grant from the Kansas Bioscience Authority Eminent Scholar Program and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship; The Australian Twin Cohort Study was supported by National Health and Medical Research Council of Australia; The KBCP was financially supported by the special Government Funding (EVO) of Kuopio University Hospital grants, Cancer Fund of North Savo, the Finnish Cancer Organizations, the Academy of Finland and by the strategic funding of the University of Eastern Finland; The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society and the Sigrid Juselius Foundation. The population allele and genotype frequencies were obtained from the data source funded by the Nodic Center of Excellence in Disease Genetics based on samples regionally selected from Finland, Sweden and Denmark. Funding Information: Breast Cancer Research Foundation, National Institutes of Health (R01 CA128978), National Cancer Institute specialized program of research excellence (SPORE) in Breast Cancer (P50 CA116201); Mayo Cancer Genetic Epidemiology Training Grant (R25 CA092049). MCBCS was supported by the David and Margaret T. Grohne Family Foundation and the Ting Tsung and Wei Fong Chao Foundation; The GENICA was funded by the Federal Ministry of Education and Research (BMBF) Germany (01KW9975/5, 01KW9976/8, 01KW9977/0 and 01KW0114), the Robert Bosch Foundation, Stuttgart, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Institute for Prevention and Occupational Medicine of the German Social Accident
PY - 2014/4
Y1 - 2014/4
N2 - Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10-8) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10-4] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10-9) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10-69). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
AB - Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10-8) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 [rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10-4] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10-9) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46-4.70, P = 4.8 × 10-69). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
UR - http://www.scopus.com/inward/record.url?scp=84901988970&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84901988970&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgt404
DO - 10.1093/carcin/bgt404
M3 - Article
C2 - 24325915
AN - SCOPUS:84901988970
VL - 35
SP - 1012
EP - 1019
JO - Carcinogenesis
JF - Carcinogenesis
SN - 0143-3334
IS - 5
ER -