Validation of Metabolic Signature Epigenetic Biomarkers for Colon Cancer Risk

描述（由申请人提供）：人类基因组测序计划期待已久的承诺之一是鉴定与人类常见疾病有关的基因。人类遗传学家已经确定了与2型糖尿病、哮喘和许多其他常见疾病有关的基因。尽管取得了这些成功，但识别这些“常见疾病基因”的转化影响很小，因为每个缺陷基因的携带者患病的相对风险很小。尽管这一事实对遗传学家来说并不奇怪，但它提出了一个问题，即可以在遗传风险数据中添加哪些类型的信息，以提高对任何特定疾病的最高或最低风险的预测能力。在这种情况下，人们对“表观遗传标记”增加遗传风险预测价值的潜力非常感兴趣

DESCRIPTION (provided by applicant): One of the long-awaited promises of the human genome sequencing project is the identification of genes involved in common human disease. Human geneticists have identified genes involved in type 2 diabetes, asthma, and many other common diseases. Despite these successes, there has been little translational impact of identifying these "common disease genes" because the relative risk of developing disease for carriers of each defective gene is small. Although this fact is not surprising to geneticists, it bgs the question of what type of information could be added to genetic risk data to increase the predictive power of who is at highest or lowest risk for any particular disease. In this vein, ther is great interest in the potential for "epigenetic markers" to add predictive value to genetic risk data. There is perhaps no better case for a major role for epigenetic effects in common disease than colon cancer. Colon cancer accounts for more than 10% of all invasive cancer cases in the United States and more than 100,000 new cases are diagnosed each year. It is the third most common cancer in both men and women and the third leading cause of cancer deaths. Epigenetic alterations are associated with both increased risk of disease and tumor progression. Moreover, there is compelling evidence linking environmental influences such as western diets and cigarette smoking with increased risk of colon cancer. Our hypothesis is that systemic epigenetic differences and environmentally-induced epigenetic changes are associated with increased risk of colon cancer and that these differences can be distinguished in colon mucosa that appears otherwise "normal". We published the results of a pilot experiment that compared the normal colon mucosa of cancer patients with the normal colon mucosa of individuals who did not have cancer or colon polyps and found highly significant differences in DNA methylation at many of the genes involved in the metabolism of lipids and carbohydrates (dietary components that may be involved in increased risk of colon cancer), as well as insulin signaling. In this project, we propose to validate a set of these DNA methylation differences that are likely to result from dietary factors in cancer-prone individuals. If validated in an independent group of patients, this set of DNA methylation differences will constitute an epigenetic metabolic signature of colon cancer risk. A collection of such biomarkers would constitute a quantitative, clinically useful biochemical tool to assess cancer risk.