Khunluck Tueanjai, Kukongviriyapan Veerapol, Puapairoj Anucha, Khuntikeo Narong, Senggunprai Laddawan, Zeekpudsa Ponsilp, Prawan Auemduan
Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Thailand E-mail :
Asian Pac J Cancer Prev. 2014;15(1):299-304. doi: 10.7314/apjcp.2014.15.1.299.
Cholangiocarcinoma (CCA), a malignancy of biliary duct with a very poor prognosis, is the leading cause of cancer death in countries of the Mekong subregion. Liver fluke infection is the main etiological factor, but genetic variation has been recognized as also important in conferring susceptibility to CCA risk. Nuclear factor (erythroid derived 2)-like 2 (NRF2) is a key transcription factor in detoxification and antioxidant defense. Emerging evidence has demonstrated that genetic polymorphisms in the NRF2 gene may be associated with cancer development. The objectives of this study were to investigate the association of NRF2 genetic polymorphism with CCA risk and to evaluate the influence of the NRF2 genotype on survival time of affected patients. Single nucleotide polymorphisms (SNPs) of the NRF2 gene, including rs6726395: A/G, rs2886161: C/T, rs1806649: C/T, and rs10183914: C/T, were analyzed using TaqMan® SNP genotyping assays. Among 158 healthy northeastern Thai subjects, the allele frequencies were 41, 62, 94, and 92%, respectively. The correlation of NRF2 SNPs and CCA risk was analyzed in the 158 healthy subjects and 198 CCA patients, using unconditional logistic regression. The results showed that whereas the NRF2 SNPs were not associated with CCA risk (p>0.05), Kaplan-Meier analysis of 88 intrahepatic CCA patients showed median survival time with rs6726395 genotypes of GG and AA/AG to be 344±138 (95%CI: 73-615) days and 172±37 (95%CI: 100-244) days, respectively, (p<0.006). On multivariate Cox proportional hazard analysis, the GG genotype of rs6726395 was found to be associated with longer survival with a hazard ratio of 0.54 (95%CI: 0.31-0.94). In addition, non-papillary adenocarcinoma was associated with poor survival with a hazard ratio of 2.09 (95%CI: 1.16-3.75). The results suggest that the NRF2 rs6726395 polymorphism can be a potential prognostic biomarker for CCA patients.
胆管癌（CCA）是一种预后极差的胆管恶性肿瘤，是湄公河次区域国家癌症死亡的主要原因。肝吸虫感染是主要病因，但基因变异在赋予CCA发病易感性方面也被认为很重要。核因子（红系衍生2）样2（NRF2）是解毒和抗氧化防御中的关键转录因子。新出现的证据表明，NRF2基因中的基因多态性可能与癌症发展有关。本研究的目的是调查NRF2基因多态性与CCA风险的关联，并评估NRF2基因型对受影响患者生存时间的影响。使用TaqMan®SNP基因分型检测法分析了NRF2基因的单核苷酸多态性（SNP），包括rs6726395：A/G、rs2886161：C/T、rs1806649：C/T和rs10183914：C/T。在158名泰国东北部健康受试者中，等位基因频率分别为41%、62%、94%和92%。在158名健康受试者和198名CCA患者中，使用非条件逻辑回归分析NRF2 SNP与CCA风险的相关性。结果显示，虽然NRF2 SNP与CCA风险无关（p>0.05），但对88例肝内CCA患者进行的Kaplan-Meier分析显示，rs6726395基因型为GG和AA/AG的患者中位生存时间分别为344±138（95%CI：73 - 615）天和172±37（95%CI：100 - 244）天，（p<0.006）。在多变量Cox比例风险分析中，发现rs6726395的GG基因型与较长生存时间相关，风险比为0.54（95%CI：0.31 - 0.94）。此外，非乳头状腺癌与较差的生存相关，风险比为2.09（95%CI：1.16 - 3.75）。结果表明，NRF2 rs6726395多态性可能是CCA患者潜在的预后生物标志物。
