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