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

Kristen S. Purrington(Mayo Clinic in Florida), Susan Slager(Mayo Clinic in Florida), Diana Eccles(Mayo Clinic), Drakoulis Yannoukakos(National Centre of Scientific Research "Demokritos"), Peter A. Fasching(University of California, Los Angeles), Penelope Miron(Dana-Farber Cancer Institute), Jane Carpenter(The University of Sydney), Jenny Chang‐Claude(German Cancer Research Center), Nicholas G. Martin(QIMR Berghofer Medical Research Institute), Grant W. Montgomery(QIMR Berghofer Medical Research Institute), Vessela Kristensen(Oslo University Hospital), Hoda Anton‐Culver(University of California, Irvine), Paul J. Goodfellow(Barnes-Jewish Hospital), William Tapper(Mayo Clinic), Sajjad Rafiq(Mayo Clinic), Susan M. Gerty(Mayo Clinic), Lorraine Durcan(Mayo Clinic), Irene Konstantopoulou(National Centre of Scientific Research "Demokritos"), Florentia Fostira(National Centre of Scientific Research "Demokritos"), Athanassios Vratimos(National Centre of Scientific Research "Demokritos"), Paraskevi Apostolou(National Centre of Scientific Research "Demokritos"), Irene Konstanta(National Centre of Scientific Research "Demokritos"), Vassiliki Kotoula(Molecular Oncology (United States)), Sotiris Lakis(Aristotle University of Thessaloniki), Meletios Α. Dimopoulos(National and Kapodistrian University of Athens), Dimosthenis Skarlos(Metropolitan Hospital), Dimitrios Pectasides(National and Kapodistrian University of Athens), George Fountzilas(Aristotle University of Thessaloniki), Matthias W. Beckmann(Friedrich-Alexander-Universität Erlangen-Nürnberg), Alexander Hein(Friedrich-Alexander-Universität Erlangen-Nürnberg), Matthias Ruebner(Friedrich-Alexander-Universität Erlangen-Nürnberg), Arif B. Ekici, Arndt Hartmann, R. Schulz-Wendtland(Friedrich-Alexander-Universität Erlangen-Nürnberg), Stefan P. Renner(Friedrich-Alexander-Universität Erlangen-Nürnberg), Wolfgang Janni(University Hospital Ulm), Brigitte Rack(Ludwig-Maximilians-Universität München), Christoph Scholz(University Hospital Ulm), Julia Neugebauer(Ludwig-Maximilians-Universität München), Ulrich Andergassen(Ludwig-Maximilians-Universität München), Michael P. Lux(Friedrich-Alexander-Universität Erlangen-Nürnberg), Lothar Haeberle(Friedrich-Alexander-Universität Erlangen-Nürnberg), Christine L. Clarke(The University of Sydney), Nirmala Pathmanathan(Westmead Hospital), Anja Rudolph(German Cancer Research Center), Dieter Flesch‐Janys(Universität Hamburg), Stefan Nickels(Universität Hamburg), Janet E. Olson(Mayo Clinic in Florida), James N. Ingle, Curtis Olswold(Mayo Clinic in Florida), Seth W. Slettedahl(Mayo Clinic in Florida), Jeanette E. Eckel‐Passow(Mayo Clinic in Florida), S. Keith Anderson(Mayo Clinic in Florida), Daniel W. Visscher(Mayo Clinic), Victoria Cafourek(Mayo Clinic in Florida), Hugues Sicotte(Mayo Clinic in Florida), Naresh Prodduturi(Mayo Clinic in Florida), Elisabete Weiderpass(Cancer Council Victoria), Leslie Bernstein(City of Hope), Argyrios Ziogas(University of California, Irvine), Jennifer Ivanovich(Barnes-Jewish Hospital), Graham G. Giles(Cancer Council Victoria), Laura Baglietto(Cancer Council Victoria), Melissa C. Southey(The University of Melbourne), Veli-Matti Kosma(University of Eastern Finland), H.-P. Fischer(University of Bonn), Malcolm Reed(Yorkshire Cancer Research), Simon S. Cross(University of Sheffield), Sandra Deming-Halverson(Vanderbilt University), Martha J. Shrubsole(Vanderbilt University), Qiuyin Cai(Vanderbilt University), Xiao‐Ou Shu(Vanderbilt University), Mary B. Daly(Fox Chase Cancer Center), JoEllen Weaver(University of Pennsylvania), Eric A. Ross(Fox Chase Cancer Center), Jennifer R. Klemp(University of Kansas Medical Center), Priyanka Sharma(University of Kansas Medical Center), Diana Torres(German Cancer Research Center), Thomas Rüdiger(Städtisches Klinikum Karlsruhe), Heidrun Wölfing(Städtisches Klinikum Karlsruhe), Hans-Ulrich Ulmer(Klinikum Mittelbaden), Asta Försti(German Cancer Research Center), Thaer Khoury, Shicha Kumar(Roswell Park Comprehensive Cancer Center), Robert Pilarski, Charles L. Shapiro(The Ohio State University), Dario Greco, Päivi Heikkilä, Kristiina Aittomäki, Carl Blomqvist(Helsinki University Hospital), Astrid Irwanto(Genome Institute of Singapore), Jianjun Liu(Genome Institute of Singapore), V. Shane Pankratz(Mayo Clinic in Florida), Xianshu Wang(Mayo Clinic), Gianluca Severi(Cancer Council Victoria), Arto Mannermaa(University of Eastern Finland), Douglas F. Easton(University of Cambridge), Per Hall(Karolinska Institutet), Hiltrud Brauch(Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology), Angela Cox(Yorkshire Cancer Research), Wei Zheng(Vanderbilt University), Andrew K. Godwin(University of Kansas Medical Center), Ute Hamann(German Cancer Research Center), Christine B. Ambrosone(Roswell Park Comprehensive Cancer Center), Amanda E. Toland(Cancer Genetics (United States)), Heli Nevanlinna, Celine M. Vachon(Mayo Clinic in Florida), Fergus J. Couch(Mayo Clinic)
Carcinogenesis
December 9, 2013
10.1093/carcin/bgt404
Cited by 160Open Access
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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.

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