Journal Article

A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer

Christoph Sachse, Gillian Smith, Murray J.V. Wilkie, Jennifer H. Barrett, Robin Waxman, Frank Sullivan, David Forman, D. Timothy Bishop and C.Roland Wolf

in Carcinogenesis

Volume 23, issue 11, pages 1839-1850
Published in print November 2002 | ISSN: 0143-3334
Published online November 2002 | e-ISSN: 1460-2180 | DOI:
A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer

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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.

Keywords: 95% CI, 95% confidence interval; AA, aromatic amine; CYP, cytochrome P450; EPHX1, microsomal epoxide hydrolase; GST, glutathione S-transferase; HA, heterocyclic amine; MTHFR, methylenetetrahydrofolate reductase; NAT2, N-acetyl transferase 2; NQO1, NAD(P)H:quinone oxidoreductase; OR, odds ratio; PAH, polycyclic aromatic hydrocarbon; PCR, polymerase chain reaction; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; RFLP, restriction fragment length polymorphism; SNP, single nucleotide polymorphism; SULT, sulfotransferase.

Journal Article.  8462 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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