Kuo Sung-Hsin, Yang Shi-Yi, You San-Lin, Lien Huang-Chun, Lin Ching-Hung, Lin Po-Han, Huang Chiun-Sheng
Department of Oncology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan.
Oncotarget. 2017 Mar 28;8(13):20925-20938. doi: 10.18632/oncotarget.14995.
In this study, we investigated whether single nucleotide polymorphisms (SNPs) identified by genome-wide association study (GWAS) (MAP3K1, FGFR2, TNRC9, HCN1, and 5p12), and SNPs involved in the metabolism of estrogen (CYP19, COMT, ESR1, and UGT1A1), tamoxifen (CYP2C9, CYP2C19, CYP3A5, and CYP2D6), and chemotherapeutic agents (ABCB1, ALDH3A1, and CYP2B6) are associated with the prognoses of 414 hormone receptor (HR)-positive early breast cancers with negative or 1 to 3 nodal metastases. At a median follow-up period of 10.6 years, 363 patients were alive, and 51 (12.3%) had died. Multiple-adjusted hazard ratios (aHRs) and the corresponding 95% confidence intervals for distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS) in association with the genotypes of 34 SNPs from the above-mentioned 16 genes were evaluated, using the stepwise selection Cox model. We found that the SNP, ESR1-codon325 rs1801132 (G/G+G/C), was associated with a longer DDFS, whereas UGT1A1 rs4148323 (A/A+A/G), and HCN1 rs981782 (A/A+A/C) were significantly associated with poorer DDFS. MAP3K1 rs889312 (C/C) and CYP2B6 rs3211371 (T/C) were significantly associated with poor DFS, DDFS and OS. Among premenopausal women, MAP3K1 rs889312 (C/C), CYP2B6 rs3211371 (T/C), CYP2B6 rs4802101 (T/T), ABCB1 rs2032582 (C/C), and ALDH3A1 rs2231142 (G/G) were significantly associated with poor DDFS, DFS, or OS. Our results provide additional evidence that genetic polymorphisms observed in SNPs are associated with the prognoses of patients with HR-positive breast cancers; this may indicate different treatment strategies for these patients.
在本研究中,我们调查了通过全基因组关联研究(GWAS)鉴定出的单核苷酸多态性(SNP)(MAP3K1、FGFR2、TNRC9、HCN1和5p12),以及参与雌激素(CYP19、COMT、ESR1和UGT1A1)、他莫昔芬(CYP2C9、CYP2C19、CYP3A5和CYP2D6)和化疗药物(ABCB1、ALDH3A1和CYP2B6)代谢的SNP,是否与414例激素受体(HR)阳性、伴有阴性或1至3个淋巴结转移的早期乳腺癌患者的预后相关。在中位随访期10.6年时,363例患者存活,51例(12.3%)死亡。使用逐步选择Cox模型评估了与上述16个基因的34个SNP基因型相关的远处无病生存期(DDFS)、无病生存期(DFS)和总生存期(OS)的多因素调整风险比(aHR)及相应的95%置信区间。我们发现,SNP ESR1 - 密码子325 rs1801132(G/G + G/C)与更长的DDFS相关,而UGT1A1 rs4148323(A/A + A/G)和HCN1 rs981782(A/A + A/C)与较差的DDFS显著相关。MAP3K1 rs889312(C/C)和CYP2B6 rs3211371(T/C)与较差的DFS、DDFS和OS显著相关。在绝经前女性中,MAP3K1 rs889312(C/C);CYP2B6 rs3211371(T/C);CYP2B6 rs4802101(T/T);ABCB1 rs2032582(C/C)和ALDH3A1 rs2231142(G/G)与较差的DDFS、DFS或OS显著相关。我们的结果提供了额外的证据,表明SNP中观察到的基因多态性与HR阳性乳腺癌患者的预后相关;这可能表明针对这些患者的不同治疗策略。