Biomarkers of Methionine Metabolism and Risk for Colorectal Adenoma

描述（由申请人提供）：结直肠癌是最常见的恶性肿瘤之一，是美国癌症死亡的第二大原因。这些癌症大多是由腺瘤性息肉引起的。参与单碳代谢和甲基化反应异常的因素在以前的结直肠肿瘤研究中都有涉及。蛋氨酸代谢是单碳代谢的关键组成部分，它全面参与了包括DNA和RNA甲基化在内的大多数生理甲基化反应。s -腺苷型同型半胱氨酸（SAH）是同型半胱氨酸的前体，被认为是蛋氨酸代谢变化的一个比同型半胱氨酸更敏感的标志物。此外，s -腺苷蛋氨酸（SAM）与SAH的比例是甲基化能力的标志，较低的SAM: SAH与DNA低甲基化增加有关。然而，这两种标志物都没有被评估与癌症风险的关系。我们假设高SAH水平和低SAM: SAH比值与结直肠腺瘤的风险增加有关。在这项拟议的研究中，我们将通过开展巢式病例对照研究来评估这些假设，该研究使用的血浆样本是田纳西州结直肠息肉研究（TCPS; P50CA95103）的一部分，这是一项正在进行的基于结肠镜检查的结直肠腺瘤病例对照研究。我们将测量265例病例和265例匹配对照的SAH和SAM水平。在应用程序中提出的假设是新颖的，并基于强大的生物学合理性。这项研究的结果不仅有助于了解单碳代谢和结直肠肿瘤的发生，而且还有助于开发一种敏感的生物标志物，用于识别具有成本效益的结直肠筛查和化学预防的高风险个体。

DESCRIPTION (provided by applicant): Colorectal cancer is one of the most common malignancies and is the second leading cause of cancer death in the United States. Most of these cancers arise from adenomatous polyps. Factors involved in one-carbon metabolism and aberrations in methylation reactions have been implicated in previous studies of colorectal neoplasia. Methionine metabolism is a key component in one-carbon metabolism and it is integrally involved in most physiologic methylation reactions including DNA and RNA methylation. S-adenosylhomocysteine (SAH), the precursor to homocysteine, has been proposed as a more sensitive marker of alterations in methionine metabolism than homocysteine. Additionally, the ratio of S-adenosylmethionine (SAM) to SAH is a marker of methylating capacity and a lower SAM: SAH is related to increased DNA hypomethylation. However, neither of these markers has been evaluated in relation to cancer risk. We hypothesize that a high SAH level and a low SAM: SAH ratio are associated with an increased risk of colorectal adenoma. In this proposed study, we will evaluate these hypotheses by conducting a nested case-control study using plasma samples collected as part of the Tennessee Colorectal Polyp Study (TCPS; P50CA95103), an on-going colonoscopy-based case-control study of colorectal adenoma. We will measure SAH and SAM levels in 265 cases and 265 matched controls. The hypotheses proposed in the application are novel and based on strong biological plausibility. Results from this study will not only be useful to understand one-carbon metabolism and colorectal neoplasia but also be informative for developing a sensitive biomarker for identifying high-risk individuals for cost-effective colorectal screening and chemoprevention.