Journal Article

Glutathione <i>S</i>-transferase T1 polymorphisms are associated with outcome in colorectal cancer

R. Rajagopal, M. Deakin, A.S. Fawole, J.B. Elder, J. Elder, V. Smith, R.C. Strange and A.A. Fryer

in Carcinogenesis

Volume 26, issue 12, pages 2157-2163
Published in print December 2005 | ISSN: 0143-3334
Published online July 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi195
Glutathione S-transferase T1 polymorphisms are associated with outcome in colorectal cancer

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Colorectal cancer (CRC) remains a significant cause of mortality accounting for ∼10% of all deaths from malignancy in the western world. Polymorphism in the glutathione S-transferase GSTT1 gene has been associated with CRC risk in some but not all studies. In this study, we examined associations between GSTT1 genotypes and CRC risk, and prognosis in 361 cases and 881 unrelated controls. GSTT1 null was associated with a small but significant increase in risk (P = 0.0006, odds ratio (OR) = 1.65, 95% confidence interval (CI) = 1.22–2.24). GSTT1 null was also associated with a significantly younger age at diagnosis (mean 65.2 years) compared with GSTT1 A (mean 67.6 years, P = 0.031). There were no significant associations between GSTT1 genotypes and clinical factors (e.g. Dukes stage, differentiation and tumour node metastasis classification) in the total case group. However, following stratification by age (<70 versus ≥70 years at diagnosis), in the patients diagnosed <70 years of age, GSTT1 null was more common in Dukes grade A/B tumours (P = 0.046), stage T1/T2 tumours (P = 0.053) and those with a pushing margin (P = 0.066). We also identified associations between GSTT1 null and increased prevalence of host lymphocyte response, particularly in the younger patients (P = 0.036). Furthermore, GSTT1 null was associated with improved survival in younger patients (P = 0.017, hazards ratio (HR) = 0.52, 95% CI = 0.31–0.89) but poorer survival in older patients (P = 0.017, HR = 1.89, 95% CI = 1.12–3.20). We proposed a model based on the dual functionality of GSTT1 to explain these contrasting results. We suggest that the null genotype is associated with improved immune response in younger patients, but poorer detoxification in older patients. These findings may also provide an explanation for the contrasting finding of other studies on the role of this gene in CRC.

Keywords: CI, confidence interval; CRC, colorectal cancer; GST, glutathione S-transferase; HLR, host lymphocyte reaction; HR, hazard ratio; OR, odds ratio; PCR, polymerase chain reaction; SCE, sister chromatid exchange; SD, standard deviation; TNM, tumour node metastasis

Journal Article.  4431 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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