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。这些癌症大多数是由腺瘤性息肉引起的。参与一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已经被发现。甲硫氨酸代谢是一碳代谢的关键组成部分，并且其整体参与大多数生理甲基化反应，包括DNA和RNA甲基化。S-腺苷高半胱氨酸（SAH）是高半胱氨酸的前体，已被认为是比高半胱氨酸更敏感的蛋氨酸代谢改变的标志物。此外，S-腺苷甲硫氨酸（SAM）与SAH的比率是甲基化能力的标志，并且较低的SAM：SAH与增加的DNA低甲基化有关。然而，这些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比值与结直肠腺瘤风险增加相关。在这项拟议的研究中，我们将通过使用田纳西结直肠息肉研究（TCPS; P50 CA 95103）的一部分采集的血浆样本进行巢式病例对照研究来评估这些假设，TCPS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。申请中提出的假设是新颖的，并且基于强生物相容性。这项研究的结果不仅有助于了解一碳代谢和结直肠肿瘤，而且有助于开发一种敏感的生物标志物，用于识别高风险个体，以进行成本效益高的结直肠筛查和化学预防。

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.