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

et al. (2013) 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 8(7): e69039. doi:10.1371/journal.pone.0069039 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 Ching-Yu Lai 0 1 Ling-Ling Hsieh 0 1 Fung-Chang Sung 0 1 Reiping Tang 0 1 Chyi-Huey Bai 0 1 Fang-Yang Wu 0 1 Hung-Yi Chiou 0 1 Chih-Ching Yeh 0 1 0 Editor: Xiao-Ping Miao, MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology , China 1 1 Department of Public Health, College of Public Health, China Medical University , Taichung City, Taiwan , 2 Department of Public Health, Chang Gung University , Guieshan, Taoyuan County , Taiwan , 3 Colorectal Section, Chang Gung Memorial Hospital , Guieshan, Taoyuan County , Taiwan , 4 School of Public Health, College of Public Health and Nutrition, Taipei Medical University , Taipei City, Taiwan , 5 Center of Excellence for Cancer Research, Taipei Medical University , Taipei City , Taiwan 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 = 1.182.95). 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. - Competing Interests: The authors have declared that no competing interests exist. After surgery, most metastatic colorectal cancer (CRC) patients receive an adjuvant chemotherapy regimen consisting of combination therapy using 5-fluorouracil (FU) and oxaliplatin (FOLFOX) or leucovorin (LV) for 6 to 8 mo to reduce the probability of tumor recurrence and prolong survival [13]. The functional single-nucleotide polymorphisms (SNPs) in drug-targeted genes, including xenobiotic-metabolizing and DNA-repair genes, correlate with variability in clinical outcome in multiple types of cancer [48]. The identification of genetic markers may help identify patients who may benefit from chemotherapy and reduce potential toxicity. Variable chemosensitivity may involve the detoxification pathway, including the glutathione S-transferases (GSTs). The GSTs are multigene families of enzymes that inactivate electrophilic xenobiotics by conjugation with glutathione, preventing DNA damage and adduct formation [9]. Interindividual differences in GST activity may be mediated by genetic polymorphisms [912]. The structural deletion polymorphisms in GSTM1 and GSTT1 result in the loss of enzyme-catalyzed detoxification activity [10], and are predictors of clinical outcome in gastric cancer patients receiving platinum/5-FU chemotherapy [13]. In addition, the reduced glutathione conjugation resulting from polymorphism in the GSTP1 Ile105Val (rs1695) coding region may be associated with an increased survival in CRC patients treated with oxaliplatin/5-FU [14,15]. Various DNA-repair enzymes play important roles in preventing treatment resistance and protecting the genome against carcinogenesis [1619]. The expression of the base excision repair (BER) gene family is triggered by internal oxidative stress and DNA damage [20]. The BER pathway involves the X-ray crosscomplementing group 1 gene XRCC1 [21]. The XRCC1 protein directly associates with polymerase beta, DNA ligase III, and poly (ADP-ribose) polymerase (PARP) in single-strand break-repair processes that may play a role in tumor cell sensitivity to 5-FU treatment [22,23]. The XRCC3 protein, a member of the Rad51related enzyme family, contributes to the maintenance of chromosome stability through DNA double-strand break/recombination repair in homologous recombination [24]. The nucleotide excision repair (NER) gene family functions within a range of structurally unrelated DNA lesions and DNA adducts [16,17]. The xeroderma pigmentosum complementation group D (XPD) protein, a member of the NER family functions in sensing, binding, and the subsequent recruitment of repair-related factors [5]. Previous studies have shown that the allelic variants XRCC1 Arg399Gln (rs25487), XRCC3 Thr241Met (rs861539), and XPD Lys751Gln (rs13181) are associated with DNA adduct levels and repair capacity [5,25,26]. Therefore, these polymorphisms of DNA-repair genes may affect clinical outcomes in cancer patients receiving chemotherapy [7,13,20,27,28]. Our previous studies have shown that the null genotypes of GSTM1 and GSTT1, GSTP1 Ile105Val, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln allelic variants are associated with significantly increased risks of CRC [2932]. However, other previous reports of associations between GST and DNA-repair allelic variants and clinical outcomes in CRC have been conflicting [6,11,3335]. Whether these conflicting findings have been due to tissue-specific differences in gene expression between colonic and rectal tumors is unclear [36] because reports of stratified analyses based on the site of the CRC tumor are scant. Therefore, in our present study, we investigated the relationship between the allelic variants of relevant GST and DNA-repair genes and the chemotherapeutic outcomes in a retrospective CRC cohort who received adjuvant chemotherapy in Taiwan to determine whether differences exist among the associatio (...truncated)