有机阴离子转运多肽1B3基因遗传变异与TA方案新辅助化疗乳腺癌患者预后的关联研究

Association study of genetic variations in SLCO1B3 gene with prognosis in breast cancer patients treated with neoadjuvant chemotherapy of TA regimen

目的探讨有机阴离子转运多肽1B3(OATP1B3)基因单核苷酸多态性(SNP)与TA方案(蒽环类药物+紫杉类药物)新辅助化疗乳腺癌患者预后的关系。方法439例采用TA方案行新辅助化疗的女性乳腺癌患者,化疗前每人抽取静脉血2 ml,筛选标签SNP,采用Sequenom MassARRAY基因分型平台进行标签SNP分型,并分析标签SNP与乳腺癌患者预后的关系。采用多因素Cox回归分析计算进展或死亡风险比(HR)及其95%可信区间(CI)。结果筛选出7个标签SNP,分别是rs11045689、rs200104106、rs3764006、rs3834935、rs4149117、rs7305323和rs73241801。rs11045689与患者无进展生存、总生存有关(P值分别为0.008和0.015)。与携带rs11045689 GG基因型的患者相比,携带rs11045689 AA基因型患者的无进展生存和总生存较差,进展风险比(HR)及其95% CI为1.39(1.11~1.75),死亡HR及其95% CI为1.38(1.04~1.83)。与携带rs73241801 CC基因型的患者相比,携带rs73241801 TT基因型患者的总生存较好(P=0.041),死亡HR及其95%CI为0.65(0.44~0.94)。累积分析显示,携带风险等位基因的数量与患者的无进展生存、总生存均有关(P值分别为0.012和0.017)。与携带0~1个风险等位基因的患者相比,携带4个风险等位基因患者的无进展生存和总生存较差,进展HR及其95% CI为1.37(1.09~1.72),死亡HR及其95% CI为1.36(1.02~1.81)。结论SLCO1B3基因rs11045689和rs73241801与TA方案新辅助化疗乳腺癌患者的预后有关,可作为预测乳腺癌新辅助化疗患者预后的生物标志物。

Objective To assess the association of single nucleotide polymorphisms (SNPs) in SLCO1B3 gene with prognosis of breast cancer (BC) patients treated with neoadjuvant chemotherapy of TA regimen (taxane and antharcycline drugs). Methods 439 female BC patients were recruited and treated with neoadjuvant chemotherapy of TA regimen. A blood sample (2 ml) of peripheral blood was collected from each patient before chemotherapy. Tagging SNPs (tag-SNPs) were selected. We investigated the association of tag-SNPs with prognosis, by Sequenom Mass ARRAY system platform, characterizing tag-SNPs. The hazard ratio (HR) and 95% confidence interval (CI) for progression or death were calculated by multivariable-adjusted Cox regression model. Results Seven tag-SNPs (rs11045689, rs200104106, rs3764006, rs3834935, rs4149117, rs7305323 and rs73241801) were selected for study. Compared with individuals carrying the rs11045689 GG genotype, individuals carrying rs11045689 AA genotype performed worse PFS and OS, with the HR (95% CI) for progression being 1.39 (1.11~1.75) and the HR (95% CI) for death being 1.38 (1.04~1.83). Compared with individuals carrying the rs73241801 CC genotype, individuals carrying rs73241801 TT genotype performed better OS (P=0.041), with the HR (95% CI) for death being 0.65 (0.44~0.94). The number of risk allele was significantly associated with PFS (P=0.012) and OS (P=0.017) of BC patients by accumulation analysis. Compared with individuals carrying one or less than one risk allele, individuals carrying four risk alleles performed worse PFS and OS, with the HR (95% CI) for progression being 1.37 (1.09~1.72) and the HR (95% CI) for death being 1.36 (1.02~1.81). Conclusion The variations of rs11045689 and rs73241801 in SLCO1B3 gene were significantly associated with prognosis of BC patients treated with neoadjuvant chemotherapy of TA regimen, which might serve as biomarkers for predicting prognosis of BC patients treated with neoadjuvant chemotherapy.