title: A pharmacogenetic study to investigate the role of dietary carcinogens in the etiology of colorectal cancer.
abstract: 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 EPHX1(His113) 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.
authors.affiliation: Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Christoph
authors.initials: C
authors.lastname: Sachse
authors.forename: Gillian
authors.initials: G
authors.lastname: Smith
authors.forename: Murray J V
authors.initials: MJ
authors.lastname: Wilkie
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Barrett
authors.forename: Robin
authors.initials: R
authors.lastname: Waxman
authors.forename: Frank
authors.initials: F
authors.lastname: Sullivan
authors.forename: David
authors.initials: D
authors.lastname: Forman
authors.forename: D Timothy
authors.initials: DT
authors.lastname: Bishop
authors.forename: C Roland
authors.initials: CR
authors.lastname: Wolf
mesh_terms: D000230:Adenocarcinoma / Q000139:chemically induced* / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000588:Amines / Q000009:adverse effects / Q000493:pharmacokinetics; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000502:physiology; D001711:Biotransformation; D002273:Carcinogens / Q000009:adverse effects* / Q000493:pharmacokinetics; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced* / Q000235:genetics; D015179:Colorectal Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000453:epidemiology / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology; D004032:Diet / Q000009:adverse effects*; D004739:England; D004851:Epoxide Hydrolases / Q000235:genetics / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics / Q000502:physiology; D006571:Heterocyclic Compounds / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000502:physiology; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000502:physiology; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000235:genetics / Q000502:physiology; D011084:Polycyclic Aromatic Hydrocarbons / Q000009:adverse effects / Q000493:pharmacokinetics; D015238:Sulfotransferases / Q000235:genetics / Q000502:physiology
chemical_list: D000588:Amines; D002273:Carcinogens; D006571:Heterocyclic Compounds; D007527:Isoenzymes; D011084:Polycyclic Aromatic Hydrocarbons; D003577:Cytochrome P-450 Enzyme System; D000587:Oxidoreductases Acting on CH-NH Group Donors; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D005982:Glutathione Transferase; D015238:Sulfotransferases; D004851:Epoxide Hydrolases