Sachse Christoph, Smith Gillian, Wilkie Murray J V, Barrett Jennifer H, Waxman Robin, Sullivan Frank, Forman David, Bishop D Timothy, Wolf C Roland
Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Carcinogenesis. 2002 Nov;23(11):1839-49. doi: 10.1093/carcin/23.11.1839.
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 CYP1A12C (OR = 2.15, 95% CI 1.36-3.39) and homozygosity for GSTM12/2 (OR = 1.53, 95% CI 1.16-2.02). In contrast, inheritance of the CYP2A62 (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.
结直肠癌是西方世界最常见的癌症形式之一，其易感性与多种环境和饮食风险因素有关。饮食中接触食物源性杂环胺致癌物和多环芳烃已被提出是特定的风险因素。许多多态性的I相和II相药物代谢酶负责这些化合物的代谢和处置，因此这些酶的特定等位基因变体的遗传可能会影响结直肠癌的易感性。在一项多中心病例对照研究中，对490例结直肠癌患者和593名对照（433对匹配的病例对照）进行了细胞色素P450（CYP1A1、CYP1A2、CYP1B1、CYP2A6、CYP2C9、CYP2C19和CYP2D6）、谷胱甘肽S-转移酶（GSTM1、GSTP1和GSTT1）、磺基转移酶（SULT1A1和SULT1A2）、N-乙酰转移酶2（NAT2）、NAD(P)H：醌氧化还原酶（NQO1）、亚甲基四氢叶酸还原酶（MTHFR）和微粒体环氧化物水解酶（EPHX1）基因常见多态性的基因分型。匹配的病例对照分析确定与较高结直肠癌风险相关的等位基因为CYP1A12C的携带（OR = 2.15，95% CI 1.36 - 3.39）和GSTM12/2的纯合性（OR = 1.53，95% CI 1.16 - 2.02）。相反，CYP2A62（OR = 0.51，95% CI 0.28 - 1.06）、CYP2C19*2（OR = 0.72，95% CI 0.52 - 0.98）和EPHX1(His113)等位基因的遗传与降低的癌症风险相关。我们发现NAT2基因型或与杂环胺致癌物代谢和处置相关的任何其他多态性基因与结直肠癌风险无关。该数据表明杂环胺在结直肠癌的病因学中不发挥重要作用，但接触其他致癌物如多环芳烃可能是癌症风险的重要决定因素。
