Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
Carcinogenesis. 2014 May;35(5):1012-9. doi: 10.1093/carcin/bgt404. Epub 2013 Dec 9.
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.
三阴性 (TN) 乳腺癌是一种侵袭性乳腺癌亚型，与一组独特的流行病学和遗传风险因素有关。我们进行了一项 TN 乳腺癌的两阶段全基因组关联研究（阶段 1：1529 例 TN 病例，3399 例对照；阶段 2：2148 例病例，1309 例对照），以确定影响 TN 乳腺癌风险的基因座。在第一阶段和第二阶段的联合分析中，19p13.1 和 PTHLH 基因座的变异显示出全基因组显著相关性（P < 5×10(-) (8)）。结果还表明，在第二阶段分析的单核苷酸多态性 (SNP) 中，显著相关的变异明显富集。74 个已知乳腺癌易感基因座中的 25 个变异也与 TN 乳腺癌的风险相关（P < 0.05）。与 TN 乳腺癌相关的 10 个基因座（LGR6、MDM4、CASP8、2q35、2p24.1、TERT-rs10069690、ESR1、TOX3、19p13.1、RALY）的相关性得到了确认，我们还确定了与 TN 乳腺癌相关的 15 个额外的乳腺癌基因座（P < 0.05：PEX14、2q24.1、2q31.1、ADAM29、EBF1、TCF7L2、11q13.1、11q24.3、12p13.1、PTHLH、NTN4、12q24、BRCA2、RAD51L1-rs2588809、MKL1）。此外，两个与 ESR1 中先前报道的信号无关的 SNP [rs12525163 比值比 (OR) = 1.15，P = 4.9×10(-) (4)]和 19p13.1（rs1864112 OR = 0.84，P = 1.8×10(-) (9)）与 TN 乳腺癌相关。基于已知乳腺癌风险变异的 TN 乳腺癌多基因风险评分 (PRS) 显示，PRS 最高和最低五分位数之间的 TN 乳腺癌风险差异高达 4 倍（OR = 4.03，95%置信区间 3.46-4.70，P = 4.8×10(-) (69)）。这意味着 TN 乳腺癌的绝对风险范围从 0.8%到 3.4%，表明遗传变异可用于 TN 乳腺癌风险预测。
