Association of NRF2 Polymorphism with Cholangiocarcinoma Prognosis in Thai Patients


Cholangiocarcinoma (CCA), a malignancy of biliary duct with a very poor prognosis, is the leading causeof cancer death in countries of the Mekong subregion. Liver fluke infection is the main etiological factor, butgenetic 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 withcancer development. The objectives of this study were to investigate the association of NRF2 genetic polymorphismwith CCA risk and to evaluate the influence of the NRF2 genotype on survival time of affected patients. Singlenucleotide 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 northeasternThai subjects, the allele frequencies were 41, 62, 94, and 92%, respectively. The correlation of NRF2 SNPs andCCA 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-Meieranalysis of 88 intrahepatic CCA patients showed median survival time with rs6726395 genotypes of GG andAA/AG to be 344±138 (95%CI: 73-615) days and 172±37 (95%CI: 100-244) days, respectively, (p<0.006). Onmultivariate Cox proportional hazard analysis, the GG genotype of rs6726395 was found to be associated withlonger survival with a hazard ratio of 0.54 (95%CI: 0.31-0.94). In addition, non-papillary adenocarcinoma wasassociated with poor survival with a hazard ratio of 2.09 (95%CI: 1.16-3.75). The results suggest that the NRF2rs6726395 polymorphism can be a potential prognostic biomarker for CCA patients.