Carcinogenesis, Vol. 23, No. 11, 1839-1850,
November 2002
© 2002 Oxford University Press
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION |
A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer
1 Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY,
2 Cancer Research UK Genetic Epidemiology Laboratory, St James’s University Hospital, Leeds LS9 7TF,
3 Centre for Cancer Research, Arthington House, Cookridge Hospital, Leeds LS16 6QB,
4 Tayside Centre for General Practice, University of Dundee, Dundee DD2 4AD, UK
Susceptibility to colorectal cancer, one of the most common forms of cancer in the Western world, has been associated with several environmental and dietary risk factors. Dietary exposure to food derived heterocyclic amine carcinogens and polycyclic aromatic hydrocarbons have been proposed as specific risk factors. Many polymorphic Phase I and Phase II drug metabolizing enzymes are responsible for the metabolism and disposition of these compounds and it is therefore possible that inheritance of specific allelic variants of these enzymes may influence colorectal cancer susceptibility. In a multicenter case–control study, 490 colorectal cancer patients and 593 controls (433 matched case–control pairs) were genotyped for common polymorphisms in the cytochrome P450 (CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C9, CYP2C19 and CYP2D6), glutathione S-transferase (GSTM1, GSTP1 and GSTT1), sulfotransferase (SULT1A1 and SULT1A2), N-acetyl transferase 2 (NAT2), NAD(P)H:quinone oxidoreductase (NQO1), methylenetetrahydrofolate reductase (MTHFR), and microsomal epoxide hydrolase (EPHX1) genes. Matched case-control analysis identified alleles associated with higher colorectal cancer risk as carriage of CYP1A1*2C (OR = 2.15, 95% CI 1.36–3.39) and homozygosity for GSTM1*2/*2 (OR = 1.53, 95% CI 1.16–2.02). In contrast, inheritance of the CYP2A6*2 (OR = 0.51, 95% CI 0.28–1.06), CYP2C19*2 (OR = 0.72, 95% CI 0.52–0.98) and the EPHX1His113 alleles were associated with reduced cancer risk. We found no association with colorectal cancer risk with NAT2 genotype or any of the other polymorphic genes associated with the metabolism and disposition of heterocyclic amine carcinogens. This data suggests that heterocyclic amines do not play an important role in the aetiology of colorectal cancer but that exposure to other carcinogens such as polycyclic aromatic hydrocarbons may be important determinants of cancer risk.
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