title: Polymorphisms in the glutathione S-transferase mu cluster are associated with tumour progression and patient outcome in colorectal cancer.
abstract: Glutathione S-transferase (GST) enzymes catalyse the detoxification of by-products of reactive oxygen species and are thus important in cellular defence mechanisms. The GSTs are polymorphic with allelic variants encoding isoforms with functional differences. GST polymorphism has been associated with susceptibility and clinical outcome in patients with cancer. In this retrospective cohort, we have investigated associations between common GSTM1, GSTM3 and GSTP1 polymorphisms with factors known to influence clinical out-come and patient survival in colorectal cancer. Significant linkage disequilibrium was demonstrated between GSTM1 and GSTM3 alleles (P< or =0.001). We identified no significant associations between the GSTP1(Ile105Val105) polymorphism and any clinical outcome parameters or patient survival. However significant associations were demonstrated with mu class GSTs. Those patients who were GSTM1 null presented less frequently with poorly-differentiated tumours (P=0.038). Furthermore, patients who were GSTM3 AA were less likely to present with advanced stage tumours (T-stage, P=0.036 and Dukes' classifications, P=0.012) or distant metastases (P=0.017) when examined alone. Upon further examination of the effect of linkage disequilibrium, we found that, in GSTM1 null individuals, GSTM3 AA (compared with other GSTM3 genotypes combined) had longer disease-free survival (HR=0.54, 95% CI 0.30-0.98, P=0.044). Thus, the GSTM3 AA genotype is associated with improved prognosis especially in those with GSTM1 null. Our findings suggest that the GST mu gene cluster mediates tumour characteristics and survival in patients with colorectal cancer.
authors.affiliation: Human Genomics Research Group, Institute for Science and Technology in Medicine, Keele University School of Medicine, University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire ST4 7QB, UK. s.l.holley@bemp.keele.ac.uk
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Holley
authors.forename: Ramesh
authors.initials: R
authors.lastname: Rajagopal
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hoban
authors.forename: Mark
authors.initials: M
authors.lastname: Deakin
authors.forename: Adeshina S
authors.initials: AS
authors.lastname: Fawole
authors.forename: James B
authors.initials: JB
authors.lastname: Elder
authors.forename: Jackie
authors.initials: J
authors.lastname: Elder
authors.forename: Victoria
authors.initials: V
authors.lastname: Smith
authors.forename: Richard C
authors.initials: RC
authors.lastname: Strange
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Fryer
mesh_terms: D000368:Aged; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D018572:Disease-Free Survival; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics* / Q000378:metabolism; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011379:Prognosis; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D051549:Glutathione S-Transferase pi; D005982:Glutathione Transferase; D007527:Isoenzymes; C496556:GSTP1 protein, human; C416969:glutathione transferase M3-3