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

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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, The GN, Reed MW, Cross SS, Deming-Halverson S, Shrubsole M, Cai Q, Shu XO, Daly M, Weaver J, Ross E, Klemp J, Sharma P, Torres D, Rudiger T, Wolfing H, Ulmer HU, Forsti A, Khoury T, Kumar S, Pilarski R, Shapiro CL, Greco D, Heikkila P, Aittomaki 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


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="">

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