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Carcinogenesis Advance Access published online on July 28, 2005
Carcinogenesis, doi:10.1093/carcin/bgi195
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oupjournals.org
Received March 31, 2005
Revised June 27, 2005
Accepted July 22, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Glutathione S-transferase T1 polymorphisms are associated with outcome in colorectal cancer

Rajagopal R. 1, Deakin M. 1, Fawole A. S. 1, Elder J. B. 1, Elder J. 1, Smith V. 1, Strange R. C. 1, and Fryer A. A. 1*

1 Human Genomics Research Group, Institute of Science and Technology in Medicine, University of Keele, University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire, ST4 7PA, UK

* To whom correspondence should be addressed.
Fryer A. A., E-mail: Anthony.Fryer{at}uhns.nhs.uk


  Abstract

Colorectal cancer remains a significant cause of mortality accounting for around 10% of all deaths from malignancy in the western world. Polymorphism in the glutathione S-transferase GSTT1 gene has been associated with colorectal cancer risk in some but not all studies. In this study, we examined associations between GSTT1 genotypes and colorectal cancer risk and prognosis in 361 cases and 881 unrelated controls. GSTT1 null was associated with a small but significant increase in risk (P = 0.0004, OR=1.68, 95% CI=1.26 - 2.23). 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, TNM classification) in the total case group. However, following stratification by age (<70 vs ≥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 (P = 0.017, 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 colorectal cancer.


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L. M. Dong, J. D. Potter, E. White, C. M. Ulrich, L. R. Cardon, and U. Peters
Genetic Susceptibility to Cancer: The Role of Polymorphisms in Candidate Genes
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[Abstract] [Full Text] [PDF]


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