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”的翻译影响很小，因为每个缺陷基因携带者发生疾病的相对风险很小。虽然这一事实对遗传学家来说并不奇怪，但它引发了一个问题，即什么类型的信息可以添加到遗传风险数据中，以增加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 数据也许没有比结肠癌更好的例子来说明表观遗传效应在常见疾病中的重要作用。结肠癌占美国所有浸润性癌症病例的10%以上，每年诊断出超过10万例新病例。它是男性和女性中第三大最常见的癌症，也是癌症死亡的第三大原因。表观遗传学改变与疾病风险增加和肿瘤进展相关。此外，有令人信服的证据表明，西方饮食和吸烟等环境影响与结肠癌风险增加有关。我们的假设是，系统性表观遗传差异和环境诱导的表观遗传变化与结肠癌风险增加有关，这些差异可以在结肠粘膜中区分，否则看起来“正常”。我们发表了一项初步实验的结果，该实验将癌症患者的正常结肠粘膜与没有癌症或结肠息肉的个体的正常结肠粘膜进行了比较，发现许多参与脂质和碳水化合物代谢的基因的DNA甲基化存在高度显着差异（可能参与结肠癌风险增加的饮食成分），以及胰岛素信号传导。在这个项目中，我们建议验证一组这些DNA甲基化差异，这些差异可能是由癌症易感个体的饮食因素引起的。如果在一个独立的 在结肠癌患者中，这组DNA甲基化差异将构成结肠癌风险的表观遗传代谢特征。这些生物标志物的集合将构成评估癌症风险的定量的、临床上有用的生化工具。

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.