单羧酸转运蛋白基因SNP与肝细胞肝癌预后的关联研究

Correlation between Polymorphisms of Monocarboxylate Transporter Genes and Prognosis in Hepatocellular Carcinoma

目的:探讨单羧酸转运蛋白基因(monocarboxylate transporter,MCT)单核苷酸多态性(single nucleotide polymorphism,SNPs)与肝细胞肝癌(hepatocellular carcinoma,HCC)根治术患者预后的关系。方法:运用Sequenom i PLEX分型技术对830例原发性HCC患者MCT家族(MCT1、MCT2和MCT4)基因上的8个功能性SNP位点进行基因分型,并分析这些SNP与HCC患者预后的相关性。结果:MCT1基因rs1049434位点和MCT2基因rs995343位点基因型与HCC患者总体生存期及无复发生存期均显著相关(P<0.05)。携带MCT1 AT基因型或TT基因型的患者死亡及复发风险均显著低于携带AA基因型的患者(HR=0.72;P=0.042或HR=0.64;P=0.002);携带MCT2 CT基因型或TT基因型的患者死亡及复发风险均显著高于携带CC基因型的患者(HR=1.64;P=0.018或HR=1.52;P=0.026)。而且,MCT1基因rs1049434位点和MCT2基因rs995343位点对HCC预后存在显著的累积效应,携带2个危险基因型的患者死亡及复发风险分别是没有危险基因型患者的2.16倍和2.54倍。此外,携带2个危险基因型的HCC患者在术后行TACE辅助治疗后死亡及复发风险均显著降低(P<0.05)。结论:MCT1和MCT2基因上的功能性SNP位点有可能作为HCC根治术后预后评估和TACE辅助治疗反应预测的独立标志物。

Objective： To explore the correlation between single nucleotide polymorphisms（SNPs） in monocarboxylate transporter（MCT） genes and prognosis in hepatocellular carcinoma（HCC） after radical resection. Methods： Eight functional SNPs in 3 genes（MCT1, MCT2 and MCT4） were selected and genotyped using the Sequenom i PLEX genotyping system in a cohort of 830 radical resected HCC patients. Multivariate Cox proportional hazards model and Kaplan-Meier curve were used for the prognosis analysis. Cumulative effect analysis was used for the multiple SNPs analysis. Results： Two individual SNPs, including rs1049434 in MCT1 and rs995343 in MCT2, were significantly associated with overall survival（OS） and relapse-free survival（RFS） of HCC patients（all P 〈0.05）. Patients carrying rs1049434 AT genotype or TT genotype had a significant decreased risk of death and relapse compared with those carrying the AA genotype（HR = 0.72; P = 0.042 or HR = 0.64; P = 0.002, respectively）; patients with rs995343 CT genotype or TT genotype showed significantly worse OS and RFS than did those carrying CC genotype（HR=1.64; P = 0.018 or HR=1.52; P=0.026, respectively）. MCT1rs1049434 and MCT2 rs995343 SNPs had a cumulative effect of on HCC OS and RFS（P for trend 〈0.001 for both）. Those who carrying two unfavorable genotypes（AT＋TT for MCT1 and CC for MCT2） had 2.16-fold increased risk of death or 2.54-fold increased risk of relapse compared with patients carrying no unfavorable genotypes（P=0.012 or P=0.001）. Moreover, patients carrying 2 unfavorable genotypes showed significant OS and RFS benefits from TACE therapy（all P〈0.05）. Conclusions： Our data suggest that functional SNPs in MCT1 and MCT2 genes may serve as independent prognostic biomarkers in predicting clinical outcomes and the response to TACE therapy for HCC patients who received radical resection.