Combined analysis of genetic polymorphisms in thymidylate synthase, uridine diphosphate glucoronosyltransferase and X-ray cross complementing factor 1 genes as a prognostic factor in advanced colorectal cancer patients treated with 5-fluorouracil plus oxaliplatin or irinotecan

Abstract

The aim of this study was to investigate the influence of combining thymidylate synthase (TS), X-ray cross complementing factor 1 (XRCC1) and uridine diphosphate glucoronosyltransferase (UGT1A1 * 28) polymorphism genotypes in response rate and time to progression (TTP) in metastatic colorectal cancer patients treated with 5-fluorouracil (5-FU) plus irinotecan or oxaliplatin (OXA). PCR, RFLP, allelic discrimination and direct sequencing were performed to elucidate TS, XRCC1 and UGT1A1 * 28 genotypes in blood from 71 patients. Patients with a number of favourable genotypes (NFG) ≥1 had a lower progression rate and a better TTP than patients with NFG=0 (log-rank p<0.03). In the OXA + 5-FU group, patients with the TS 5' single nucleotide polymorphism and/or XRCC1 genotypes favourable to treatment had a better TTP (log-rank p=0.02). The TS 5' tandem repeat polymorphism and the NFG were independent prognostic factors in the Cox-based multivariate analysis (p<0.03). These results confirm the influence on patient outcome of these genetic polymorphisms and the possibility of studying them together to predict the outcome in first-line treated colorectal cancer patients.

Tumor-Related Molecular Mechanisms of Oxaliplatin Resistance

“…Other genetic variants in DNA repair genes have been associated with the outcome to oxaliplatin treatment. Among them, an SNP resulting in an amino acid change (Arg to Gln) in X-ray repair cross-complementing protein 1 (XRCC1) has been shown to correlate with a worse outcome in some tumors (49,(56)(57)(58). The XPD Lys751Gln polymorphism has also been found to be associated with the outcome after oxaliplatin treatment in colorectal and gastric cancer.…”

Liver-only metastatic colorectal cancer patients and thymidylate synthase polymorphisms for predicting response to 5-fluorouracil-based chemotherapy

“…Therefore, the TS functional polymorphisms are under investigation for the possibility of optimising chemotherapy (Yong and Innocenti, 2007). Studies in patients with metastatic colorectal cancer showed that carriers of the TS 5 0 -UTR 3R (3G) and/or the TS 3 0 -UTR 6 þ alleles had adverse clinical outcomes (Pullarkat et al, 2001;Etienne et al, 2002;Park et al, 2002;Marcuello et al, 2004;Stoehlmacher et al, 2004;Martinez-Balibrea et al, 2007); however, such an association was not always detected (Lecomte et al, 2004;Jakobsen et al, 2005;Ruzzo et al, 2007a, b). Heterogeneity in clinical experimental conditions (Sorbye et al, 2007), in tumour burden (Köhne et al, 2002) and in genetic/molecular features in the presence of a multisite metastatic disease (Yokota, 2000) may explain variable results in these pharmacogenetic studies.…”

The effects of genomic polymorphisms in one-carbon metabolism pathways on survival of gastric cancer patients received fluorouracil-based adjuvant therapy

“…It was discovered that the 3R3R genotype was related with poor outcomes for colorectal cancer patients treated with 5-FU3233. For GC patients receiving 5-FU regimens, Ott et al also found that 3R3R was a risk factor for the survival34.…”