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

Abstract

IntroductionOur 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 MethodsWe 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.ResultsThe 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).ConclusionThe 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.

GSTM1, GSTT1, and GSTP1 polymorphisms and colorectal cancer risk in Polish nonsmokers

“…A meta-analysis of 36 case-control studies also detected a relationship between GSTM1 polymorphism and tumor site [ 18 ]. However other studies found no association between the GSTM1 null genotype and CRC clinicopathologic features [ 9 , 20 , 21 ].…”

Association between smoking at diagnosis and cause‐specific survival in patients with rectal cancer: Results from a population‐based analysis of 10,794 cases

“…In terms of genetic and epigenetic effects, smoking is related to increased DNA damage and reduced repair capacity, 37 and polymorphisms in DNA repair genes have been associated with colorectal cancer survival. 38 Similarly, smoking can induce aberrant DNA methylation, 39 and differential methylation has been associated with rectal cancer recurrence and survival. [40][41][42] However, whether smoking, DNA repair or methylation, and rectal cancer survival are interrelated remains unknown.…”

GSTP1 Ile105Val and XRCC1 Arg399Gln gene polymorphisms contribute to the clinical outcome of patients with advanced non-small cell lung cancer

“…Previous studies have reported that glutathione S-transferase P1 (GSTP1) and X-ray repair cross-complementing group 1 (XRCC1) genetic variations may influence the efficacy of chemotherapy in various cancers, such as colon cancer, gastric cancer, and ovarian cancer (Khrunin et al, 2010;Ji et al, 2013;Lai et al, 2013;Zaanan et al, 2014). Currently, many studies reported the role of GSTP1 and XRCC1 genetic polymorphisms in the clinical outcome of NSCLC, but the results are inconclusive.…”