Gynecologic Oncology Group Statistical and Data Center, Buffalo, NY 14263, USA.
Gynecol Oncol. 2012 Mar;124(3):575-81. doi: 10.1016/j.ygyno.2011.11.022. Epub 2011 Nov 21.
Efflux transporters of the ATP-binding cassette (ABC) family are major determinants of chemoresistance in tumor cells. This study examined associations between functional variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes in patients with epithelial ovarian/primary peritoneal cancer (EOC/PPC) following platinum and taxane-based chemotherapy.
Sequenom iPLEXTMGOLD Assay and MALDI-TOF platform were used to genotype the non-synonymous G2677T/A (rs2032582; encoding Ala893Ser/Thr) and synonymous C3435T (rs1045642; encoding Ile1145Ile) variants in ABCB1, the non-synonymous G1249A variant in ABCC2 (rs2273697; encoding Val417Ile), and the non-synonymous C421A variant in ABCG2 (rs2231142; encoding Q141K, Gln141Lys) in normal DNA from up to 511 women in Gynecologic Oncology Group (GOG) phase III trials, GOG-172 or GOG-182. Progression-free survival (PFS) and overall survival (OS) were analyzed in relation to genetic polymorphisms using Kaplan-Meier and Cox proportional hazards model.
The C421A variant (CA+AA versus CC) in ABCG2 was associated with a 6-month longer median PFS (22.7 versus 16.8 months, p=0.041). In multivariate analysis, patients with variant genotypes were at a reduced risk of disease progression (hazard ratio [HR]=0.75, 95% confidence interval [CI]=0.59-0.96, p=0.022). The association between C421A and OS was not statistically significant (HR=0.88, 95% CI=0.67-1.15, p=0.356). None of the other variants measured in either ABCB1 or ABCC2 was associated with PFS or OS.
The C421A variant in ABCG2, previously shown to be associated with enhanced protein degradation and drug sensitivity, was associated with longer PFS in advanced stage EOC/PPC patents treated with platinum+taxane-based chemotherapy. This finding requires further validation.
ATP 结合盒（ABC）家族的外排转运蛋白是肿瘤细胞化疗耐药的主要决定因素。本研究检测了 ABCB1、ABCC2 和 ABCG2 基因中的功能性变异与上皮性卵巢/原发性腹膜癌（EOC/PPC）患者接受铂类和紫杉烷类化疗后的临床结局之间的相关性。
采用Sequenom iPLEXTMGOLD assay 和 MALDI-TOF 平台，对多达 511 名妇科肿瘤学组（GOG）III 期临床试验（GOG-172 或 GOG-182）中正常 DNA 中的 ABCB1 非同义 G2677T/A（rs2032582；编码 Ala893Ser/Thr）和同义 C3435T（rs1045642；编码 Ile1145Ile）变异、ABCC2 非同义 G1249A 变异（rs2273697；编码 Val417Ile）和 ABCG2 非同义 C421A 变异（rs2231142；编码 Q141K，Gln141Lys）进行基因分型。采用 Kaplan-Meier 和 Cox 比例风险模型分析遗传多态性与无进展生存期（PFS）和总生存期（OS）的关系。
ABCG2 中的 C421A 变异（CA+AA 与 CC）与中位 PFS 延长 6 个月相关（22.7 与 16.8 个月，p=0.041）。多变量分析显示，变异基因型患者疾病进展风险降低（风险比[HR]=0.75，95%置信区间[CI]=0.59-0.96，p=0.022）。C421A 与 OS 之间的相关性无统计学意义（HR=0.88，95%CI=0.67-1.15，p=0.356）。ABCB1 或 ABCC2 中测量的其他变异均与 PFS 或 OS 无关。
先前已显示 ABCG2 中的 C421A 变异与增强的蛋白降解和药物敏感性相关，与接受铂类和紫杉烷类化疗的晚期 EOC/PPC 患者的 PFS 延长相关。这一发现需要进一步验证。
