Potter J D
Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA.
J Natl Cancer Inst. 1999 Jun 2;91(11):916-32. doi: 10.1093/jnci/91.11.916.
The epidemiology and molecular biology of colorectal cancer are reviewed with a view to understanding their interrelationship. Risk factors for colorectal neoplasia include a positive family history, meat consumption, smoking, and alcohol consumption. Important inverse associations exist with vegetables, nonsteroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy, and physical activity. There are several molecular pathways to colorectal cancer, especially the APC (adenomatous polyposis coli)-beta-catenin-Tcf (T-cell factor; a transcriptional activator) pathway and the pathway involving abnormalities of DNA mismatch repair. These are important, both in inherited syndromes (familial adenomatous polyposis [FAP] and hereditary nonpolyposis colorectal cancer [HNPCC], respectively) and in sporadic cancers. Other less well defined pathways exist. Expression of key genes in any of these pathways may be lost by inherited or acquired mutation or by hypermethylation. The roles of several of the environmental exposures in the molecular pathways either are established (e.g., inhibition of cyclooxygenase-2 by NSAIDs) or are suggested (e.g., meat and tobacco smoke as sources of specific blood-borne carcinogens; vegetables as a source of folate, antioxidants, and inducers of detoxifying enzymes). The roles of other factors (e.g., physical activity) remain obscure even when the epidemiology is quite consistent. There is also evidence that some metabolic pathways, e.g., those involving folate and heterocyclic amines, may be modified by polymorphisms in relevant genes, e.g., MTHFR (methylenetetrahydrofolate reductase) and NAT1 (N-acetyltransferase 1) and NAT2. There is at least some evidence that the general host metabolic state can provide a milieu that enhances or reduces the likelihood of cancer progression. Understanding the roles of environmental exposures and host susceptibilities in molecular pathways has implications for screening, treatment, surveillance, and prevention.
本文综述了结直肠癌的流行病学和分子生物学，旨在了解它们之间的相互关系。结直肠肿瘤的危险因素包括家族史阳性、肉类消费、吸烟和饮酒。与蔬菜、非甾体抗炎药（NSAIDs）、激素替代疗法和体育活动存在重要的负相关。结直肠癌有几种分子途径，特别是APC（腺瘤性息肉病 coli）-β-连环蛋白-Tcf（T 细胞因子；一种转录激活因子）途径和涉及 DNA 错配修复异常的途径。这些在遗传性综合征（分别为家族性腺瘤性息肉病 [FAP] 和遗传性非息肉病性结直肠癌 [HNPCC]）和散发性癌症中都很重要。还存在其他定义不太明确的途径。这些途径中任何一个关键基因的表达可能会因遗传或获得性突变或高甲基化而丧失。几种环境暴露在分子途径中的作用要么已经明确（例如，NSAIDs 对环氧合酶-2 的抑制作用），要么有相关推测（例如，肉类和烟草烟雾作为特定血源致癌物的来源；蔬菜作为叶酸、抗氧化剂和解毒酶诱导剂的来源）。即使流行病学结果相当一致，其他因素（例如体育活动）的作用仍然不清楚。也有证据表明，一些代谢途径，例如涉及叶酸和杂环胺的途径，可能会因相关基因（例如 MTHFR（亚甲基四氢叶酸还原酶）和 NAT1（N-乙酰转移酶 1）以及 NAT2）的多态性而发生改变。至少有一些证据表明，一般宿主代谢状态可以提供一个促进或降低癌症进展可能性的环境。了解环境暴露和宿主易感性在分子途径中的作用对筛查、治疗、监测和预防具有重要意义。
