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 M Eccles, Drakoulis Yannoukakos, Peter A. Fasching, Penelope Miron, Jane Carpenter, Jenny Chang-Claude, Nicholas Gordon 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 VratimosParaskevi Apostolou, Irene Konstanta, Vassiliki Kotoula, Sotiris Lakis, Meletios Athanasios 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 B 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 K Irwanto, Jianjun Liu, Vernon Shane Pankratz, Xianshu Wang, Gianluca Severi, Arto Mannermaa, Douglas F Easton, Per Hall, Hiltrud Brauch, Angela Cox, Wei Zheng, Andrew K. Godwin, Ute Hamann, Christine B. Ambrosone, Amanda Ewart Toland, Heli Nevanlinna, Celine M Vachon, Fergus J Couch, The GENICA Network

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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.

Original languageEnglish
Pages (from-to)1012-1019
Number of pages8
JournalCarcinogenesis
Volume35
Issue number5
DOIs
Publication statusPublished - May 2014
Externally publishedYes

Cite this

Purrington, K. S., Slager, S., Eccles, D. M., 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., ... The GENICA Network (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