title: Polymorphisms ofGSTP1,ERCC2andTS-3'UTR are associated with the clinical outcome of mFOLFOX6 in colorectal cancer patients.
abstract: The aim of the current study was to examine whether polymorphisms in drug metabolism genes have any clinical impact on patients treated with 5-fluorouracil (FU)/oxaliplatin for metastatic colorectal cancer (MCRC). In total, 63 patients with MCRC were recruited and treated with a modified FOLFOX6 (mFOLFOX6) treatment as a first-line chemotherapy. Polymorphisms in five drug metabolism genes and two DNA-repair genes were assessed in these patients using polymerase chain reaction (PCR), a PCR restriction fragment length polymorphism (PCR-RFLP) technique or invader techniques. These included a 28-bp tandem repeat in the 5'-untranslated region (UTR) and 6-bp deletions in the 3'-UTR of thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR; Ala677Val), glutathione S-transferase π (GSTP1; IIe105Val), GST θ1 (GSTT1; deletion) and GST μ1 (GSTM1; deletion) and the two DNA-repair genes, excision repair cross-complementing-1 (ERCC1; Asp118Asn) andERCC2(Lys751Gln). The correlation between these polymorphisms and the clinical outcome, including drug response, progression-free survival (PFS), overall survival (OS) and the incidence of peripheral neuropathy, were evaluated. Patients with theGSTP1-105 A/A genotype had poor responses to mFOLFOX6 treatment compared with those with theGSTP1-105 A/G and G/G genotypes (P=0.01). The median PFS of patients with theERCC2-751 A/A genotype tended to be longer than that of patients with theERCC2-751 A/C genotype (P=0.05). Patients with theTS-3'-UTR -6/-6 genotype had a significantly longer OS compared with patients with other genotypes (P=0.003). A statistically significant association between the incidence of peripheral neuropathy higher than grade 2 and theGSTP1-105 (P=0.03) andGSTM1genotypes (P=0.02) was identified by multivariate logistic regression analyses. Results demonstrated that polymorphisms inGSTP1-105,ERCC2-751 and the 3'-UTR ofTSmay be a statistically significant predictors of clinical outcome.GSTP1-105 andGSTM1genotypes may be useful markers of severe peripheral neuropathy in MCRC patients treated with 5-FU/oxaliplatin as first-line chemotherapy.
authors.affiliation: Department of Digestive Tract and General Surgery, Saitama Medical Center, Saitama Medical University, Kawagoe, Saitama 350-8550, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kumamoto
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Ishibashi
authors.forename: Norimichi
authors.initials: N
authors.lastname: Okada
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tajima
authors.forename: Kouki
authors.initials: K
authors.lastname: Kuwabara
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Baba
authors.forename: Norihiro
authors.initials: N
authors.lastname: Haga
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Ishida
keywords: FOLFOX; colorectal cancer; polymorphism