Tumor Site- and Stage-Specific Associations between Allelic Variants of Glutathione S-Transferase and DNA-Repair Genes and Overall Survival in Colorectal Cancer Patients Receiving 5-Fluorouracil-Based Chemotherapy

Introduction: Our retrospective cohort study investigated the effect of tumor site and stage on the associations between the allelic variants of glutathione S-transferase (GST) and DNA-repair genes and overall survival (OS) in CRC patients treated with 5-fluorouracil (5-FU)-based adjuvant chemotherapy. Material and Methods: We genotyped GSTM1, GSTT1, GSTP1 Ile105Val, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln in 491 CRC patients between 1995 and 2001. A Cox proportional-hazards model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationships between the allelic variants and OS. Survival analyses were performed for each allelic variant by using the log-rank test and Kaplan-Meier analysis. Results: The CRC patients with the XPD Gln allelic variants had poorer survival than patients with the Lys/Lys genotype (HR = 1.38, 95% CI = 1.02-1.87), and rectal cancer patients had the poorest survival among them (HR = 1.87, 95% CI = 1.18-2.95). A significantly shorter OS was observed among stage II/III colon cancer patients with the XRCC1 Gln allelic variants (HR = 1.69, 95% CI = 1.06-2.71), compared to those with XRCC1 Arg/Arg genotype. In the combined analysis of the XRCC1 and XPD genes patients with stage II/III tumors, the poorest OS occurred in colon cancer patients with the XRCC1 Gln and XPD Gln allelic variants (HR = 2.60, 95% CI = 1.19-5.71) and rectal cancer patients with the XRCC1 Arg/Arg and XPD Gln allelic variants (HR = 2.77, 95% CI = 1.25-6.17). Conclusion: The XPD and XRCC1 allelic variants may be prognostic markers for CRC patients receiving 5-FU based chemotherapy. The contributions of the XPD and XRCC1 allelic variants to OS are tumor site-and/or stage-dependent.