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

PLoS One. 2013 Jul 23;8(7):e69039. doi: 10.1371/journal.pone.0069039. Print 2013.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Antimetabolites, Antineoplastic / therapeutic use*
  • Biomarkers, Tumor
  • Cohort Studies
  • Colorectal Neoplasms* / drug therapy
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / mortality
  • Colorectal Neoplasms* / pathology
  • DNA Repair / genetics*
  • Female
  • Fluorouracil / therapeutic use*
  • Glutathione Transferase / genetics*
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Neoplasm Staging
  • Retrospective Studies

Substances

  • Antimetabolites, Antineoplastic
  • Biomarkers, Tumor
  • Glutathione Transferase
  • Fluorouracil

Grants and funding

The authors' study was supported by grants from Taipei Medical University (TMU98-AE1-B05), the National Science Council, Taiwan (NSC97-2314-B-039-020-MY3 and NSC97-2314-B-038-050-MY3), China Medical University (CMU97-259 and CMU97-156), Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH102-TD-B-111-004), and the Center of Excellence for Cancer Research of the Taiwan Department of Health at Taipei Medical University (DOH101-TD-C-111-008). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.