Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer

Kristen S. Purrington; Susan Slager; Diana Eccles; Drakoulis Yannoukakos; Peter A. Fasching; Penelope Miron; Jane Carpenter; Jenny Chang-claude; Nicholas G. Martin; Grant W. Montgomery; Vessela Kristensen; Hoda Anton-Culver; Paul Goodfellow; William J. Tapper; Sajjad Rafiq; Susan M. Gerty; Lorraine Durcan; Irene Konstantopoulou; Florentia Fostira; Athanassios Vratimos; Paraskevi Apostolou; Irene Konstanta; Vassiliki Kotoula; Sotiris Lakis; Meletios A. Dimopoulos; Dimosthenis Skarlos; Dimitrios Pectasides; George Fountzilas; Matthias W. Beckmann; Alexander Hein; Matthias Ruebner; Arif B. Ekici; Arndt Hartmann; Ruediger Schulz-wendtland; Stefan P. Renner; Wolfgang Janni; Brigitte Rack; Christoph Scholz; Julia Neugebauer; Ulrich Andergassen; Michael P. Lux; Lothar Haeberle; Christine Clarke; Nirmala Pathmanathan; Anja Rudolph; Dieter Flesch-janys; Stefan Nickels; Janet E. Olson; James N. Ingle; Curtis Olswold; Seth Slettedahl; Jeanette E. Eckel-passow; S. Keith Anderson; Daniel W. Visscher; Victoria L. Cafourek; Hugues Sicotte; Naresh Prodduturi; Elisabete Weiderpass; Leslie Bernstein; Argyrios Ziogas; Jennifer Ivanovich; Graham G. Giles; Laura Baglietto; Melissa Southey; Veli Matti Kosma; Hans Peter Fischer; Malcom W.R. Reed; Simon S. Cross; Sandra Deming-halverson; Martha Shrubsole; Qiuyin Cai; Xiao Ou Shu; Mary Daly; Jo Ellen Weaver; Eric Ross; Jennifer Klemp; Priyanka Sharma; Diana Torres; Thomas Rüdiger; Heidrun Wölfing; Hans Ulrich Ulmer; Asta Försti; Thaer Khoury; Shicha Kumar; Robert Pilarski; Charles L. Shapiro; Dario Greco; Päivi Heikkilä; Kristiina Aittomäki; Carl Blomqvist; Astrid Irwanto; Jianjun Liu; Vernon Shane Pankratz; Xianshu Wang; Gianluca Severi; Arto Mannermaa; Douglas Easton; Per Hall; Hiltrud Brauch; Angela Cox; Wei Zheng; Andrew K. Godwin; Ute Hamann; Christine Ambrosone; Amanda Ewart Toland; Heli Nevanlinna; Celine M. Vachon; Fergus J. Couch

doi:10.1093/carcin/bgt404

Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer

Kristen S. Purrington
, Susan Slager
, Diana Eccles
, Drakoulis Yannoukakos
, Peter A. Fasching
, Penelope Miron
, Jane Carpenter
, Jenny Chang-claude
, Nicholas G. Martin
, Grant W. Montgomery
, Vessela Kristensen
, Hoda Anton-Culver
, Paul Goodfellow
, William J. Tapper
, Sajjad Rafiq
, Susan M. Gerty
, Lorraine Durcan
, Irene Konstantopoulou
, Florentia Fostira
, Athanassios Vratimos

Paraskevi Apostolou, Irene Konstanta, Vassiliki Kotoula, Sotiris Lakis, Meletios A. Dimopoulos, Dimosthenis Skarlos, Dimitrios Pectasides, George Fountzilas, Matthias W. Beckmann, Alexander Hein, Matthias Ruebner, Arif B. Ekici, Arndt Hartmann, Ruediger Schulz-wendtland, Stefan P. Renner, Wolfgang Janni, Brigitte Rack, Christoph Scholz, Julia Neugebauer, Ulrich Andergassen, Michael P. Lux, Lothar Haeberle, Christine Clarke, Nirmala Pathmanathan, Anja Rudolph, Dieter Flesch-janys, Stefan Nickels, Janet E. Olson, James N. Ingle, Curtis Olswold, Seth Slettedahl, Jeanette E. Eckel-passow, S. Keith Anderson, Daniel W. Visscher, Victoria L. Cafourek, Hugues Sicotte, Naresh Prodduturi, Elisabete Weiderpass, Leslie Bernstein, Argyrios Ziogas, Jennifer Ivanovich, Graham G. Giles, Laura Baglietto, Melissa Southey, Veli Matti Kosma, Hans Peter Fischer, Malcom W.R. Reed, Simon S. Cross, Sandra Deming-halverson, Martha Shrubsole, Qiuyin Cai, Xiao Ou Shu, Mary Daly, Jo Ellen Weaver, Eric Ross, Jennifer Klemp, Priyanka Sharma, Diana Torres, Thomas Rüdiger, Heidrun Wölfing, Hans Ulrich Ulmer, Asta Försti, Thaer Khoury, Shicha Kumar, Robert Pilarski, Charles L. Shapiro, Dario Greco, Päivi Heikkilä, Kristiina Aittomäki, Carl Blomqvist, Astrid Irwanto, Jianjun Liu, Vernon Shane Pankratz, Xianshu Wang, Gianluca Severi, Arto Mannermaa, Douglas Easton, Per Hall, Hiltrud Brauch, Angela Cox, Wei Zheng, Andrew K. Godwin, Ute Hamann, Christine Ambrosone, Amanda Ewart Toland, Heli Nevanlinna, Celine M. Vachon, Fergus J. Couch

Mayo Clinic Rochester, MN
University of Southampton, Faculty of Medicine
Demokritos National Centre for Scientific Research
University of California at Los Angeles
Friedrich-Alexander University Erlangen-Nürnberg
Dana-Farber Cancer Institute
Westmead Millennium Institute for Medical Research
German Cancer Research Center
Queensland Institute of Medical Research
University of Oslo
University of California, Irvine
Washington University St. Louis
Aristotle University of Thessaloniki
National and Kapodistrian University of Athens
'Metropolitan' Hospital
Ulm University
Ludwig Maximilian University of Munich
Westmead Hospital
University of Hamburg
University of Tromsø
Folkhalsan
Cancer Registry of Norway Institute of Population-Based Cancer Research
City of Hope National Med Center
Cancer Council Victoria
University of Melbourne
University of Eastern Finland
University of Bonn
Cancer Research UK
University of Sheffield
Vanderbilt University
Fox Chase Cancer Center
University of Pennsylvania
University of Kansas
Städtischen Klinikum Karlsruhe
Frauenklinik der Stadtklinik Baden-Baden
Lund University
Roswell Park Cancer Institute
Ohio State University
Helsinki University Hospital
Genome Institute of Singapore
University of Cambridge
Karolinska Institutet
University of Tübingen

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

133 Scopus citations

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
Pages (from-to)	1012-1019
Number of pages	8
Journal	Carcinogenesis
Volume	35
Issue number	5
DOIs	https://doi.org/10.1093/carcin/bgt404
State	Published - Apr 2014

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10.1093/carcin/bgt404

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Purrington, K. S., Slager, S., Eccles, D., Yannoukakos, D., Fasching, P. A., Miron, P., Carpenter, J., Chang-claude, J., Martin, N. G., Montgomery, G. W., Kristensen, V., Anton-Culver, H., Goodfellow, P., Tapper, W. J., Rafiq, S., Gerty, S. M., Durcan, L., Konstantopoulou, I., Fostira, F., ... Couch, F. J. (2014). Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer. Carcinogenesis, 35(5), 1012-1019. https://doi.org/10.1093/carcin/bgt404

@article{36ed27694a704355890b0b89e6ff0275,

title = "Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer",

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.",

author = "Purrington, \{Kristen S.\} and Susan Slager and Diana Eccles and Drakoulis Yannoukakos and Fasching, \{Peter A.\} and Penelope Miron and Jane Carpenter and Jenny Chang-claude and Martin, \{Nicholas G.\} and Montgomery, \{Grant W.\} and Vessela Kristensen and Hoda Anton-Culver and Paul Goodfellow and Tapper, \{William J.\} and Sajjad Rafiq and Gerty, \{Susan M.\} and Lorraine Durcan and Irene Konstantopoulou and Florentia Fostira and Athanassios Vratimos and Paraskevi Apostolou and Irene Konstanta and Vassiliki Kotoula and Sotiris Lakis and Dimopoulos, \{Meletios A.\} and Dimosthenis Skarlos and Dimitrios Pectasides and George Fountzilas and Beckmann, \{Matthias W.\} and Alexander Hein and Matthias Ruebner and Ekici, \{Arif B.\} and Arndt Hartmann and Ruediger Schulz-wendtland and Renner, \{Stefan P.\} and Wolfgang Janni and Brigitte Rack and Christoph Scholz and Julia Neugebauer and Ulrich Andergassen and Lux, \{Michael P.\} and Lothar Haeberle and Christine Clarke and Nirmala Pathmanathan and Anja Rudolph and Dieter Flesch-janys and Stefan Nickels and Olson, \{Janet E.\} and Ingle, \{James N.\} and Curtis Olswold and Seth Slettedahl and Eckel-passow, \{Jeanette E.\} and Anderson, \{S. Keith\} and Visscher, \{Daniel W.\} and Cafourek, \{Victoria L.\} and Hugues Sicotte and Naresh Prodduturi and Elisabete Weiderpass and Leslie Bernstein and Argyrios Ziogas and Jennifer Ivanovich and Giles, \{Graham G.\} and Laura Baglietto and Melissa Southey and Kosma, \{Veli Matti\} and Fischer, \{Hans Peter\} and Reed, \{Malcom W.R.\} and Cross, \{Simon S.\} and Sandra Deming-halverson and Martha Shrubsole and Qiuyin Cai and Shu, \{Xiao Ou\} and Mary Daly and Weaver, \{Jo Ellen\} and Eric Ross and Jennifer Klemp and Priyanka Sharma and Diana Torres and Thomas R{\"u}diger and Heidrun W{\"o}lfing and Ulmer, \{Hans Ulrich\} and Asta F{\"o}rsti and Thaer Khoury and Shicha Kumar and Robert Pilarski and Shapiro, \{Charles L.\} and Dario Greco and P{\"a}ivi Heikkil{\"a} and Kristiina Aittom{\"a}ki and Carl Blomqvist and Astrid Irwanto and Jianjun Liu and Pankratz, \{Vernon Shane\} and Xianshu Wang and Gianluca Severi and Arto Mannermaa and Douglas Easton and Per Hall and Hiltrud Brauch and Angela Cox and Wei Zheng and Godwin, \{Andrew K.\} and Ute Hamann and Christine Ambrosone and Toland, \{Amanda Ewart\} and Heli Nevanlinna and Vachon, \{Celine M.\} and Couch, \{Fergus J.\}",

note = "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{\textquoteright}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",

year = "2014",

month = apr,

doi = "10.1093/carcin/bgt404",

language = "English",

volume = "35",

pages = "1012--1019",

journal = "Carcinogenesis",

issn = "0143-3334",

publisher = "Oxford University Press",

number = "5",

}

Purrington, KS, Slager, S, Eccles, D, Yannoukakos, D, Fasching, PA, Miron, P, Carpenter, J, Chang-claude, J, Martin, NG, Montgomery, GW, Kristensen, V, Anton-Culver, H, Goodfellow, P, Tapper, WJ, Rafiq, S, Gerty, SM, Durcan, L, Konstantopoulou, I, Fostira, F, Vratimos, A, Apostolou, P, Konstanta, I, Kotoula, V, Lakis, S, Dimopoulos, MA, Skarlos, D, Pectasides, D, Fountzilas, G, Beckmann, MW, Hein, A, Ruebner, M, Ekici, AB, Hartmann, A, Schulz-wendtland, R, Renner, SP, Janni, W, Rack, B, Scholz, C, Neugebauer, J, Andergassen, U, Lux, MP, Haeberle, L, Clarke, C, Pathmanathan, N, Rudolph, A, Flesch-janys, D, Nickels, S, Olson, JE, Ingle, JN, Olswold, C, Slettedahl, S, Eckel-passow, JE, Anderson, SK, Visscher, DW, Cafourek, VL, Sicotte, H, Prodduturi, N, Weiderpass, E, Bernstein, L, Ziogas, A, Ivanovich, J, Giles, GG, Baglietto, L, Southey, M, Kosma, VM, Fischer, HP, Reed, MWR, Cross, SS, Deming-halverson, S, Shrubsole, M, Cai, Q, Shu, XO, Daly, M, Weaver, JE, Ross, E, Klemp, J, Sharma, P, Torres, D, Rüdiger, T, Wölfing, H, Ulmer, HU, Försti, A, Khoury, T, Kumar, S, Pilarski, R, Shapiro, CL, Greco, D, Heikkilä, P, Aittomäki, K, Blomqvist, C, Irwanto, A, Liu, J, Pankratz, VS, Wang, X, Severi, G, Mannermaa, A, Easton, D, Hall, P, Brauch, H, Cox, A, Zheng, W, Godwin, AK, Hamann, U, Ambrosone, C, Toland, AE, Nevanlinna, H, Vachon, CM & Couch, FJ 2014, 'Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer', Carcinogenesis, vol. 35, no. 5, pp. 1012-1019. https://doi.org/10.1093/carcin/bgt404

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 - https://www.scopus.com/pages/publications/84901988970

U2 - 10.1093/carcin/bgt404

DO - 10.1093/carcin/bgt404

M3 - Article

C2 - 24325915

AN - SCOPUS:84901988970

SN - 0143-3334

VL - 35

SP - 1012

EP - 1019

JO - Carcinogenesis

JF - Carcinogenesis

IS - 5

ER -

Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer

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