Alcohol and Colorectal Cancer: The Influence of Inherited and Nutritional Factors

描述（由申请人提供）：饮酒是结直肠癌的既定风险因素。然而，尚不清楚生物学机制是什么，以及是否存在易感亚群。酒精摄入量和结肠癌之间的正相关关系主要限于有阳性结肠直肠癌家族史的女性，基于这一初步发现，我们建议描述该关系的剂量反应和时间，以研究遗传因素对结肠直肠腺瘤和结肠直肠癌风险的修饰作用。如果酒精通过一碳代谢途径起作用，那么自1996年以来，在谷物产品中添加叶酸后，酒精摄入对结直肠癌发生的影响可能会减弱。由于大多数关于酒精和结直肠腺瘤/癌的流行病学研究都是在叶酸强化前随访的人群中进行的，因此我们建议评估酒精和结直肠腺瘤/癌之间的关联是否与强化后一样强。即使强化后整体相关性减弱，饮酒与结直肠腺瘤/癌之间的正相关性在特别易感人群中仍可能持续存在。有结直肠癌家族史者可能是易感人群之一。其他易感人群包括亚甲基四氢叶酸还原酶（MTHFR）677变异基因型的人群和那些参与一碳代谢的其他营养素摄入量低的人群，包括维生素B6和B12，蛋氨酸，胆碱和甜菜碱。我们对女性和男性进行了大型前瞻性研究，现有饮酒和饮酒模式的数据以及6，000多例结直肠腺瘤和约2，800例结直肠癌病例，以极其节省时间和成本的方式解决这些科学假设。本研究可提供更好的了解家族史的性质，并为有家族史的高易感人群提供有用的癌症预防指南。这项拟议的工作还将提供机会，通过叶酸强化状态对酒精和结直肠癌风险进行首次流行病学评估，这将澄清酒精对一碳代谢的参与和重要性，并确定在当前高叶酸摄入状态下饮酒对结直肠癌的影响。 公共卫生相关性：在这项拟议的工作中，我们打算探讨遗传和饮食因素对饮酒和结直肠腺瘤/癌症之间的关联在女性和男性的大型流行病学研究的影响。通过阐明这些因素对酒精和结直肠癌风险的作用，这项研究可以帮助识别易受酒精不良影响的人群，并指导人们预防癌症。

DESCRIPTION (provided by applicant): Alcohol consumption is an established risk factor for colorectal cancer. However, it is not clear what the biological mechanisms are and if there are susceptible sub-populations. Building on the initial finding that a positive association between alcohol intake and colon cancer was largely restricted to women with a positive family history of colorectal cancer, we propose to characterize the dose-response and timing of the association to examine the modifying role of inherited factors in relation to colorectal adenoma and colorectal cancer risk. If alcohol operates through the one-carbon metabolism pathways, it is plausible that the influence of alcohol intake on colorectal carcinogenesis may have weakened after folate fortification of grain products, which was largely in place since 1996. Because most epidemiologic studies on alcohol and colorectal adenoma/cancer have been conducted in populations with follow-up prior to folate fortification, we propose to evaluate whether the association between alcohol and colorectal adenoma/cancer would be as strong as post fortification. Even if the overall association is weakened after the fortification, the positive association between alcohol consumption and colorectal adenoma/cancer may still persist among particularly susceptible populations. Those with family history of colorectal cancer may be one of the susceptible populations. Other susceptible populations include those with methylene-tetrahydrofolate reductase (MTHFR) 677 variant genotype and those with low intake of other nutrients involved in one-carbon metabolism, including vitamins B6 and B12, methionine, choline, and betaine. We have large prospective studies of women and men with existing data on alcohol consumption and drinking pattern and over 6,000 colorectal adenoma and about 2,800 colorectal cancer cases to address these scientific hypotheses in an extremely time- and cost- effective manner. This study may provide better insight on the nature of family history and provide useful cancer prevention guideline for the highly susceptible population of those with a family history. This proposed work will also provide opportunities for the first epidemiologic evaluation of alcohol and colorectal cancer risk by folate fortification status, which will clarity the involvement and importance of alcohol on one-carbon metabolism and determine the effect of alcohol consumption on colorectal cancer in current high-folate intake status. Public Health Relevance: In this proposed work, we intend to explore the influence of inherited and dietary factors on the association between alcohol consumption and colorectal adenoma/cancer in large epidemiological studies of women and men. By clarifying the role of these factors on alcohol and colorectal cancer risk, this study can help identifying populations susceptible to the adverse effect of alcohol and guiding people in cancer prevention.