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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. and Montgomery, Grant W., et al. (2014) In Carcinogenesis 35(5). p.1012-1019
Abstract
In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.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 x 10(-) (8)) in stage 1 and 2 combined. Results also suggested a substantial... (More)
In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.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 x 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 x 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 x 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 x 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. (Less)
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Carcinogenesis
volume
35
issue
5
pages
1012 - 1019
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Oxford University Press
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  • wos:000336043800006
  • scopus:84901988970
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0143-3334
DOI
10.1093/carcin/bgt404
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English
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2014-07-01 07:40:59
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@article{d2ef36e5-9e24-47a3-98ce-10aa022ada54,
  abstract     = {In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk relative to women with few variants.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 &lt; 5 x 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 &lt; 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 &lt; 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 x 10(-) (4)] and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 x 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 x 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 Slager, Susan and Eccles, Diana and Yannoukakos, Drakoulis and Fasching, Peter A. and Miron, Penelope and Carpenter, Jane and Chang-Claude, Jenny and Martin, Nicholas G. and Montgomery, Grant W. and Kristensen, Vessela and Anton-Culver, Hoda and Goodfellow, Paul and Tapper, William J. and Rafiq, Sajjad and Gerty, Susan M. and Durcan, Lorraine and Konstantopoulou, Irene and Fostira, Florentia and Vratimos, Athanassios and Apostolou, Paraskevi and Konstanta, Irene and Kotoula, Vassiliki and Lakis, Sotiris and Dimopoulos, Meletios A. and Skarlos, Dimosthenis and Pectasides, Dimitrios and Fountzilas, George and Beckmann, Matthias W. and Hein, Alexander and Ruebner, Matthias and Ekici, Arif B. and Hartmann, Arndt and Schulz-Wendtland, Ruediger and Renner, Stefan P. and Janni, Wolfgang and Rack, Brigitte and Scholz, Christoph and Neugebauer, Julia and Andergassen, Ulrich and Lux, Michael P. and Haeberle, Lothar and Clarke, Christine and Pathmanathan, Nirmala and Rudolph, Anja and Flesch-Janys, Dieter and Nickels, Stefan and Olson, Janet E. and Ingle, James N. and Olswold, Curtis and Slettedahl, Seth and Eckel-Passow, Jeanette E. and Anderson, S. Keith and Visscher, Daniel W. and Cafourek, Victoria L. and Sicotte, Hugues and Prodduturi, Naresh and Weiderpass, Elisabete and Bernstein, Leslie and Ziogas, Argyrios and Ivanovich, Jennifer and Giles, Graham G. and Baglietto, Laura and Southey, Melissa and Kosma, Veli-Matti and Fischer, Hans-Peter and Reed, Malcom W. R. and Cross, Simon S. and Deming-Halverson, Sandra and Shrubsole, Martha and Cai, Qiuyin and Shu, Xiao-Ou and Daly, Mary and Weaver, JoEllen and Ross, Eric and Klemp, Jennifer and Sharma, Priyanka and Torres, Diana and Rudiger, Thomas and Wolfing, Heidrun and Ulmer, Hans-Ulrich and Försti, Asta and Khoury, Thaer and Kumar, Shicha and Pilarski, Robert and Shapiro, Charles L. and Greco, Dario and Heikkila, Paivi and Aittomaki, Kristiina and Blomqvist, Carl and Irwanto, Astrid and Liu, Jianjun and Pankratz, Vernon Shane and Wang, Xianshu and Severi, Gianluca and Mannermaa, Arto and Easton, Douglas and Hall, Per and Brauch, Hiltrud and Cox, Angela and Zheng, Wei and Godwin, Andrew K. and Hamann, Ute and Ambrosone, Christine and Toland, Amanda Ewart and Nevanlinna, Heli and Vachon, Celine M. and Couch, Fergus J.},
  issn         = {0143-3334},
  language     = {eng},
  number       = {5},
  pages        = {1012--1019},
  publisher    = {Oxford University Press},
  series       = {Carcinogenesis},
  title        = {Genome-wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple-negative breast cancer},
  url          = {http://dx.doi.org/10.1093/carcin/bgt404},
  volume       = {35},
  year         = {2014},
}