Methionine metabolism in esophageal adenocarcinoma carcinogenesis

 描述（由申请方提供）：食管腺癌（EA）是美国和西方国家最常见的食管癌，在过去30年中发病率增加了675%。五年生存率非常低，不到20%。因此，进行研究以了解病因并制定预防策略是非常重要的。大多数EA出现在巴雷特食管（BE），一种肠上皮化生的情况下，其中食管的正常衬里被直肠型组织取代。BE和EA的病因学知之甚少，很少有可改变的风险因素已被确定。EA被认为是BE通过一个化生-异型增生-癌序列的累积遗传和表观遗传修饰，包括DNA甲基化的畸变。最近的研究表明，低甲基化可能是一个关键因素，出现在癌的早期. 最近，我们在一项基于人群的病例对照研究中发现，饮食中摄入的参与一碳代谢的维生素（OCM;叶酸和维生素B6）与BE和EA风险呈负相关，这表明OCM是食管癌发生的一个重要危险因素，其影响可能在癌发生过程的早期。OCM的一个重要组成部分是蛋氨酸循环。特别是，蛋氨酸代谢在DNA和RNA甲基化中是必不可少的。S-腺苷甲硫氨酸（SAM）是甲硫氨酸的直接代谢产物，是体内几乎所有甲基化反应的甲基供体。血液SAM与组织中的DNA甲基化（包括整体甲基化）呈正相关。 我们最近在两项研究中发现，较高的血浆SAM水平与肿瘤形成风险降低相关;较高的SAM水平与结直肠腺瘤（癌症前体）减少相关，并与低度和侵袭性前列腺癌的风险降低相关，这一结果与腺瘤发现一致。因此，有初步数据表明SAM可能在癌发生的早期和晚期阶段产生影响。结合我们的初步数据，饮食OCM因素有BE和EA风险的作用，我们假设，蛋氨酸循环代谢，特别是SAM和SAH有EA致癌作用。我们建议在一项初步研究中使用来自BE和EA的基于人群的病例对照研究的血浆样本来检验这一假设。分析将包括218例BE病例、208例EA病例和259例健康对照。这将是第一项评估这一新假设的研究。

 DESCRIPTION (provided by applicant): Esophageal adenocarcinoma (EA) is the most common form of esophageal cancer in the US and western countries and incidence has increased by 675% over the past 30 years. Five-year survival is very poor at less than 20%. Thus, it is very critical to conduct studies to understand the etiology and to develop prevention strategies. Most EA arises in Barrett's Esophagus (BE), a condition of intestinal metaplasia in which the normal lining of the esophagus is replaced by intestinal-type tissue. The etiology of BE and EA are poorly understood and very few modifiable risk factors have been identified. EA is presumed to arise from BE through a metaplasia-dysplasia-carcinoma sequence of cumulative genetic and epigenetic modifications including aberrations in DNA methylation. Recent studies suggest hypo- methylation may be a key factor that appears early in carcinogenesis. Very recently, we found dietary intakes of vitamins involved in one-carbon metabolism (OCM; folate and vitamin B6) were inversely associated with both BE and EA risk in a population-based case-control study suggesting that OCM is an important risk factor in esophageal carcinogenesis and its effect may be early in the carcinogenesis process. An important component of OCM is the methionine cycle. In particular, methionine metabolism is essential in DNA and RNA methylation. S-adenosyl-methionine (SAM), the direct metabolite of methionine, is the methyl donor for nearly all methylation reactions in the body. Blood SAM is positively linked to DNA methylation, including global methylation, in tissues. We recently found higher plasma SAM levels were associated with decreased neoplasia risk in two studies; higher SAM levels were associated decreased colorectal adenoma, a cancer precursor, and with decreased risk of both low-grade and aggressive prostate cancers, a result consistent with the adenoma findings. Thus, there are preliminary data that SAM may have an effect at early and late stages of carcinogenesis. Combined with our preliminary data that dietary OCM factors have a role in BE and EA risk, we hypothesize that methionine cycle metabolism, and specifically SAM and SAH have a role in EA carcinogenesis. We propose to test this hypothesis in a pilot study using plasma samples from a population-based case-control study of BE and EA. Included in the analysis will be 218 BE cases, 208 EA cases, and 259 healthy controls. This will be the first study to evaluate this novel hypothesis.