Polymorphisms of GSTP1, GSTT1, GSTM1, MTHFR, TS, ERCC1, and ERCC2 in metastatic colorectal cancer treated by first-line mFOLFOX6 chemotherapy

Abstract

e14628 Background: It was reported that determining functional polymorphisms of genes involved in drug-metabolising pathways and DNA repair may be useful for predicting the response to 5-FU/oxaliplatin chemotherapy in Caucasian patients with metastatic colorectal cancer. This study was performed to examine whether determining these polymorphisms had any clinical value in Asian patients with colorectal cancer receiving 5-FU/oxaliplatin therapy. Methods: Genomic DNA was extracted from peripheral blood lymphocytes (n=25) or colonic mucosa (n=47) in Japanese patients with metastatic colorectal cancer who were receiving first-line therapy with the modified FOLFOX6 regimen followed by FOLFIRI (n=42). Polymorphisms of 5 genes involved in drug metabolism (glutathione S-transferase (GST) P1 (IIe 105 Val), GSTT1 deletion, and GSTM1 deletion, methylenetetrahydrofolate reductase (MTHFR) (Ala 677 Val), and a 6-base pair (bp) deletion in the 3’-untranslated region (UTR) of thymidylate synthase (TS)), and polymorphisms of two DNA repair genes (excision repair cross complementing group 1 (ERCC1): Asp 118 Asn and ERCC2: Lys 751 Gln) were assessed in these patients by PCR-RFLP or the invader technique. Correlations between polymorphisms of these genes and the response to therapy were evaluated. Results: The distribution of the genotypes of GSTP1, GSTT1, TS, ERCC1, and ERCC2 in the present Japanese patients (but not that of GSTM1 or MTHFR), differed significantly from the distribution of these genotypes in a Caucasian population. The response rate and progression-free survival were not correlated with any of the functional polymorphisms investigated. However, patients who had both alleles containing the 6-bp nucleotide fragment in the 3’UTR of TS showed significantly shorter overall survival than those who had at least one allele without the 6-bp nucleotide fragment (p=0.03). Conclusions: These results suggest that 3’UTR polymorphism of TS may be an important predictor of overall survival for Japanese patients with metastatic colorectal cancer receiving first-line 5-FU/oxaliplatin therapy. No significant financial relationships to disclose.