Explorative study to identify novel candidate genes related to oxaliplatin efficacy and toxicity using a DNA repair array

Abstract

PURPOSE: To identify new polymorphisms (single nucleotide polymorphisms, SNPs) in DNA repair pathways that are associated with efficacy and toxicity in patients receiving oxaliplatin and capecitabine for advanced colorectal cancer (ACC). METHODS: We studied progression-free survival (PFS) in 91 ACC patients, of whom germ-line DNA was isolated and genotyped using an Asper Biotech array. Overall survival (OS) and toxicity were studied as secondary end points. A step-wise selection of SNPs was performed, involving univariate and multivariate log-rank tests and Cox regression analysis, with age and performance status as covariates. RESULTS: A total of 81 SNPs in 46 genes on the array were selected for further analysis, based on genotyping success rates and minor allele frequencies. After step-wise selection, we found that homozygosity for the ataxia telangiectasia mutated gene (ATM) rs1801516 or excision repair cross-complementing gene (ERCC5) rs1047768 SNPs was associated with shorter PFS; however there were no significant associations (P40.01) with OS or toxicity. DISCUSSION: This is the first study describing the pathway gene approach for the selection of new candidate genes involved in oxaliplatin efficacy and toxicity. The results suggest that the ATM and ERCC5 genes may be associated with oxaliplatin efficacy in ACC.

MTHFR Glu429Ala and ERCC5 His46His Polymorphisms Are Associated with Prognosis in Colorectal Cancer Patients: Analysis of Two Independent Cohorts from Newfoundland

“…In the presence of increased concentration of 5,10-MTHF, the inhibition of thymidine synthesis and thus the efficacy of 5-FU is expected to increase and this has been demonstrated in vitro in human colon cancer cells [42]. However, in multiple prognostic studies, statistical association of the MTHFR Glu429Ala polymorphism with response to treatment with 5-FU based chemotherapy in colorectal cancer patients was not detected [25], [26], [43]–[49] suggesting that MTHFR Glu429Ala polymorphism may not affect the efficacy of 5-FU based treatments. In the present study too, no significant association of MTHFR Glu429Ala was found in patients treated with 5-FU based chemotherapy (although we cannot fully rule out the possibility of insufficient study power to detect an effect).…”

Determining Timing of Hepatectomy for Colorectal Cancer with Distant Metastasis According to Imaging-Based Tumor Shrinkage Ratio

“…RNF8 has been shown to act as a tumor suppressor in mice by mediating repair of DNA DSBs, thereby preventing genomic instability 9, 36. DSBs are the main mechanism of oxaliplatin-induced cell death 37 and are associated with oxaliplatin efficacy in advanced CRC 38. Thus, RNF8 was suggested to be associated with the cell growth inhibitory effect of oxaliplatin.…”

GSTP1, ERCC1 and ERCC2 Polymorphisms, Expression and Clinical Outcome of Oxaliplatin-based Adjuvant Chemotherapy in Colorectal Cancer in Chinese Population

“…However, there still some contradicting reports. A study conducted in Netherlands showed GSTP1 codon 105 polymorphism is not associated with oxaliplatin efficacy in advanced colorectal cancer patients (Kweekel et al, 2009;Kim et al, 2011). The lack of a predictive role for the GSTP1 polymorphism may be due to the difference in tissue-specificity and drug-specificity of GSTP1 isoenzymes, and the variation in ethnicities and study design.…”