Methionine metabolism in esophageal adenocarcinoma carcinogenesis

 描述(申请人提供)：食管腺癌(EA)是美国和西方国家最常见的食道癌形式，在过去的30年里，发病率增加了675%。五年存活率非常低，不到20%。因此，进行研究以了解病因和制定预防策略是非常关键的。大多数EA发生在Barrett‘s食道(BE)，这是一种肠化生的情况，在这种情况下，食道的正常衬里被肠型组织取代。BE和EA的病因知之甚少，几乎没有可改变的危险因素被识别出来。EA被认为是由BE通过累积的遗传和表观遗传修饰的化生-异型增生-癌序列产生的，包括DNA甲基化的异常。最近的研究表明，低甲基化可能是癌症早期出现的一个关键因素。最近，我们在一项基于人群的病例对照研究中发现，参与一碳代谢的维生素(OCM；叶酸和维生素B6)的摄入量与BE和EA的风险呈负相关，这表明OCM是食道癌发生的重要危险因素，其作用可能在癌变过程的早期。甲硫氨酸循环是OCM的一个重要组成部分。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-蛋氨酸是蛋氨酸的直接代谢物，是体内几乎所有甲基化反应的甲基供体。血液中的SAM与DNA甲基化呈正相关，包括组织中的全局甲基化。我们最近在两项研究中发现，较高的血浆SAM水平与肿瘤风险的降低有关；较高的SAM水平与结直肠腺瘤(一种癌症先兆)的减少以及低级别和侵袭性前列腺癌的风险降低相关，这一结果与腺瘤的研究结果一致。因此，有初步数据表明，SAM可能在癌变的早期和晚期起作用。结合我们的初步数据，饮食中的OCM因素在BE和EA的风险中起作用，我们假设蛋氨酸循环代谢，特别是SAM和SAH在EA的致癌中起作用。我们建议使用BE和EA人群病例对照研究中的血浆样本在一项先导性研究中验证这一假设。分析中将包括218例BE病例、208例EA病例和259名健康对照。这将是评估这一新假说的第一项研究。

 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.