Association of NRF2 Polymorphism with Cholangiocarcinoma Prognosis in Thai Patients

Abstract

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.

Cholelithiasis and the risk of intrahepatic cholangiocarcinoma: a meta-analysis of observational studies

“…In addition, the prevalence of hepatitis infection, which is also a risk factor for ICC, is higher in East Asian countries than in Western countries, which is consistent with the higher prevalence of ICC in East Asian countries [ 4 , 19 – 21 ]. Also, the difference may be related to the genetic backgrounds of different races [ 28 , 29 ]. In the future, a greater number of qualified studies from different regions and different ethic groups are needed to draw a more conclusive result.…”

Molecular perturbations in cholangiocarcinoma: Is it time for precision medicine?

“…13 Although two of the selected variants (rs2143417 and rs689466) in cyclooxygenase 2 (COX2) were associated with the risk of CCA in the discovery cohort (P = 0.0003 and P = 0.005 respectively), these associations failed to reach significance in the validation cohort (P > 0.05), making the results difficult to interpret. In turn, Fingas variants, enhancer of zeste homolog 2 (EZH2) (rs24179546 15 ), nuclear factor (erythroid derived 2)-like 2 (NRF2), 16 x-ray repair crosscomplementing group (XRCC1), 17 ATP binding cassette subfamily C member 2) (ABCB2), 18 ATPase Phospholipid Transporting 8B1 (ATP8B1), 19 natural killer cell receptor G2D (NKG2D), 20 or alpha1antitrypsin (α1AT) deficiency Z heterozygosity, 21 have been linked to increased risk of CCA (Table 1) detect the risk variant and later to replicate the genetic findings.…”

Nrf2 Contributes to the Poor Prognosis and Chemoresistance

“…Nrf2 polymorphism: in addition to varying Nrf2 expression, Nrf2 polymorphism also affects the Nrf2 activity. The Nrf2 polymorphism contributes to poor prognosis in cancers, including cholangiocarcinoma [65], lung cancer [66], and breast cancer [67]. It also contributed to diseases, such as increasing the risk of acute lung injury [68,69] as well as blood pressure and cardiovascular mortality in patients with hemodialysis [70].…”