Queensland Institute of Medical Research, Brisbane, Australia.
Gynecol Oncol. 2013 Oct;131(1):8-14. doi: 10.1016/j.ygyno.2013.07.107. Epub 2013 Aug 1.
ABCB1 encodes the multi-drug efflux pump P-glycoprotein (P-gp) and has been implicated in multi-drug resistance. We comprehensively evaluated this gene and flanking regions for an association with clinical outcome in epithelial ovarian cancer (EOC).
The best candidates from fine-mapping analysis of 21 ABCB1 SNPs tagging C1236T (rs1128503), G2677T/A (rs2032582), and C3435T (rs1045642) were analysed in 4616 European invasive EOC patients from thirteen Ovarian Cancer Association Consortium (OCAC) studies and The Cancer Genome Atlas (TCGA). Additionally we analysed 1,562 imputed SNPs around ABCB1 in patients receiving cytoreductive surgery and either 'standard' first-line paclitaxel-carboplatin chemotherapy (n=1158) or any first-line chemotherapy regimen (n=2867). We also evaluated ABCB1 expression in primary tumours from 143 EOC patients.
Fine-mapping revealed that rs1128503, rs2032582, and rs1045642 were the best candidates in optimally debulked patients. However, we observed no significant association between any SNP and either progression-free survival or overall survival in analysis of data from 14 studies. There was a marginal association between rs1128503 and overall survival in patients with nil residual disease (HR 0.88, 95% CI 0.77-1.01; p=0.07). In contrast, ABCB1 expression in the primary tumour may confer worse prognosis in patients with sub-optimally debulked tumours.
Our study represents the largest analysis of ABCB1 SNPs and EOC progression and survival to date, but has not identified additional signals, or validated reported associations with progression-free survival for rs1128503, rs2032582, and rs1045642. However, we cannot rule out the possibility of a subtle effect of rs1128503, or other SNPs linked to it, on overall survival.
ABCB1 编码多药外排泵 P-糖蛋白（P-gp），并与多药耐药有关。我们全面评估了该基因及其侧翼区域与上皮性卵巢癌（EOC）临床结局的关系。
在 21 个 ABCB1 SNPs 的精细映射分析中，对标记 C1236T（rs1128503）、G2677T/A（rs2032582）和 C3435T（rs1045642）的最佳候选者进行分析，共纳入来自 13 个卵巢癌协会联盟（OCAC）研究和癌症基因组图谱（TCGA）的 4616 例欧洲侵袭性 EOC 患者。此外，我们分析了接受细胞减灭术且接受“标准”一线紫杉醇-卡铂化疗（n=1158）或任何一线化疗方案（n=2867）的患者中 ABCB1 周围的 1562 个推断 SNP。我们还评估了 143 例 EOC 患者的原发性肿瘤中的 ABCB1 表达。
精细映射显示，rs1128503、rs2032582 和 rs1045642 是最佳候选者，适用于最佳减瘤患者。然而，在对 14 项研究的数据进行分析时，我们未发现任何 SNP 与无进展生存期或总生存期之间存在显著关联。在无残留疾病患者中，rs1128503 与总生存期存在边缘关联（HR 0.88，95%CI 0.77-1.01；p=0.07）。相比之下，原发性肿瘤中 ABCB1 的表达可能会使减瘤不充分的患者预后更差。
我们的研究是迄今为止对 ABCB1 SNPs 与 EOC 进展和生存关系的最大分析，但尚未确定其他信号，也未验证 rs1128503、rs2032582 和 rs1045642 与无进展生存期相关的报道关联。然而，我们不能排除 rs1128503 或与之相关的其他 SNP 对总生存期产生轻微影响的可能性。
