Associations between genetic polymorphisms and survival for colorectal cancer patients with 5-FU chemotherapy

• Main Authors: Ching-Yu Lai, 賴慶輿
• Other Authors: 宋鴻樟
• Format: Others
• Language: zh-TW
• Published: 2014
• Online Access: http://ndltd.ncl.edu.tw/handle/64330474976804246547

博士 === 中國醫藥大學 === 公共衛生學系博士班 === 102 === Background Colorectal cancer (CRC) is the second most common cancer and the third leading cause of cancer deaths for population in Taiwan. Patients with CRC are often treated with 5-fluorouracil (5-FU) based chemotherapy after surgery. However, individual response and associated survival outcomes to these drugs may vary on genetic susceptibility. The cytotoxic effect of 5-FU is mediated by the thymidylate synthase (TYMS), dihydropyrimidine dehydrogenase (DPYD), orotate phosphoribosyltransferase (OPRT), and methylenetetrahydrofolate reductase (MTHFR). The efficacy of 5-FU may depend on the activity and concentration of these enzymes. Additionally, expressions of these enzymes are determined largely by polymorphisms on their coding genes. Epidermal growth factor receptor (EGFR) is a kind of transmembrane protein, which leads to downstream effects in gene expression causing cellular proliferation and apoptosis. Therefore, dysregulation through signal pathway may induce malignant tumors and EGFR polymorphisms would be expected to correlate with CRC survival. Polymorphisms in genes encoding glutathione S-transferase enzymes (GSTM1, GSTT1 and GSTP1) and DNA repair enzymes (XRCC1, XRCC3 and XPD) may also play important roles in the response of colorectal tumor receiving chemotherapy. Methods Between 1995 and 2001 we totally recruited 3622 histologically confirmed CRC patients, in which 499 patients had received 5-FU-based chemotherapy after surgery. We genotyped polymorphisms for TYMS (5’-UTR 2R/3R, 5’-G>C SNP in 3R, and 3’-UTR ins6/del6), OPRT G638C, DPYD A1267G, MTHFR (C677T and A1298C), EGFR (R497K, G-216T and CA repeats), GSTM1, GSTT1, GSTP1 Ile105Val, XRCC1 Arg399Gln, XRCC3 Thr241Met, and XPD Lys751Gln. We also determined the correlation between TYMS genotypes and TYMS mRNA expression levels in tumor tissues. Survival analyses on those genetic polymorphisms for CRC survivals displayed with Kaplan-Meier curves and log-rank test. The associations between genotypes or TYMS mRNA expression and survival outcomes were analyzed using Cox proportional hazard models. Stratification analyses for gender, tumor subsite, and tumor stage were also conducted. Results Colon cancer patients with the 5’-UTR high-expression genotype, compared to those with low- or moderate-expression genotype, had a significantly better overall survival (OS) (hazard ratio (HR) = 0.58, 95% confidence interval (CI) = 0.35-0.96). Furthermore, colon cancer patients simultaneously harboring the 5’-UTR G>C low- or moderate-expression genotype and 3’-UTR high-expression genotype had significantly worst OS (HR = 2.32, 95% CI = 1.20-4.51), compared to those harboring the 5’-UTR G>C high-expression genotype and 3’-UTR low-expression genotype. Better survival was related to CRC patients carrying the 3RG/ins6 haplotype (HR = 1.84), but worse survival was linked to colon cancer patients carrying the TYMS 2R or 3R/del6 and 3RG/ins6 haplotype (HR = 1.33 and 2.12, respectively). The OS was significantly longer in CRC patients with MTHFR 677 C/T+T/T genotypes compared with those with the 677 C/C genotype (HR = 0.79, 95% CI = 0.62-1.00). Although MTHFR A1298C polymorphism was not associated with OS in CRC patients, A/C+C/C genotypes showed significantly a shorter OS than those with the A/A genotype in rectal cancer patients (HR = 2.01, 95% CI = 1.34-2.80). In haplotype analysis, better survival was related to colon cancer patients carrying the MTHFR 677T-1298A haplotype (HR = 0.81, 95% CI = 0.55-0.97), but worse survival was linked to rectal cancer patients carrying the MTHFR 677C-1298C haplotype (HR = 1.58, 95% CI = 1.16-2.27). Moreover, compared to OPRT G/G genotype, G/C+C/C genotype showed a better OS in colon cancer for patients diagnosed at stage II+III patients (HR = 0.60 and HR = 0.65, respectively). Compared to patients with the S/S+S/L genotype, CRC patients with the EGFR (CA)n L/L genotype had a significant better OS (L, ≥ 20 repeats; S, < 20 repeats) (HR = 0.62, 95% CI = 0.42-0.92), particularly for patients who were males (HR = 0.63, 95% CI = 0.44-0.90), at stage IV (HR = 0.70, 95% CI = 0.49-0.99), with family history of cancer (HR = 0.55, 95% CI = 0.33-0.90) and rectal cancer (HR = 0.62, 95% CI = 0.42-0.92). Better survival was prominent for patients with the combined genotypes of EGFR (CA)n L/L, G-216T G/G, and R497K K/K (HR = 0.51, 95% CI = 0.30-0.87) than for those with the most common genotypes of the EGFR (CA)n S allele, G-216T G/G, and R497K R allele. In haplotype analysis, better survival was related to CRC and rectal cancer patients carrying the L/G/K haplotype (HR = 0.77 and 0.67, respectively). CRC patients with the XPD Gln allele had poorer survival than patients with the Lys/Lys genotype (HR = 1.38, 95% CI = 1.02-1.87), particular for rectal cancer patients (HR = 1.87, 95% CI = 1.18-2.95). A significant shorter OS was observed among stage II+III colon cancer patients with the XRCC1 Gln allele (HR = 1.69, 95% CI = 1.06-2.71), compared to those with the XRCC1 Arg/Arg genotype. In the combined analysis of the XRCC1 and XPD genes among stage II+III patients, the poorest OS was observed in colon cancer patients with the XRCC1 Gln and XPD Gln allele (HR = 2.60, 95% CI = 1.19-5.71) and in rectal cancer patients with the XRCC1 Arg/Arg and XPD Gln allele (HR = 2.77, 95% CI = 1.25-6.17). In multivariate Cox proportional hazard models showed that age, TNM stage, and 3’-UTR high expression were related to wrost survival. Beside, OPRT 638C allele, MTHFR 677T allele, and EGFR (CA)n L/L genotype were related to better survival. However, DYPD, GSTM1, GSTT1, and XRCC3 polymorphisms were not associated with OS in CRC patients even in stratification analysis. Conclusions This study was a retrospective study to investigate association between polymorphisms and survival outcomes in CRC patients treated with 5-FU based chemotherapy. We found that the polymorphisms of TYMS, MTHFR, OPRT, XRCC1, and XPD genes might serve as OS predictors. To the best of our knowledge, this is the largest study to investigate this association for the ethnic Chinese (i.e., Taiwanese) population. We have obtained innovative findings in selecting treatment regimens for CRC patients.