Insulin-like Growth Factors & Esophageal Adenocarcinoma

描述(由申请人提供)： 胰岛素样生长因子(IGF)是一种强有力的有丝分裂原，在细胞增殖、分化和凋亡的调控中发挥着关键作用。IGF通过与几个分子相互作用来发挥作用，包括细胞膜上的IGF-1受体(特别是IGF-1R)和几个IGF结合蛋白(特别是IGFBP-3)。此外，IGF-1、IGF-1R和IGFBP-3基因的多态可能与IGFS的组织浓度有关。最近有报道称，血清IGFS浓度的增加和IGFBP-3浓度的降低都会增加几种癌症的风险。我们建议利用一项正在进行的Barrett食管症(BE)患者肿瘤进展预测因素的队列研究(n=420，长达8年的随访)中收集的数据和样本来确定IGFS是否与食管腺癌(EA)的风险有关，以及一系列被证实为EA预测因素的生物标记物。受试者献血，并在基线时接受内窥镜活检、体检和面谈。自基线以来，定期进行内窥镜检查和活组织检查。目的1将确定基线血清IGF-1水平升高和IGFBP-3水平降低是否与BE肿瘤进展风险增加相关。肿瘤的进展将取决于EA的发展、高度不典型增生、4N/G2比例增加、非整倍体和/或17pLOH。目的2将确定IGF-1、IGF-1受体和IGFBP-3基因的多态是否与肿瘤进展的风险有关，以及它们是否改变了第一个目的中观察到的任何关联。二级目标将调查观察到的IGF相关性是否被EA和BE的关键风险因素改变，包括肥胖、腰臀比、非类固醇抗炎药的使用、血清硒和更年期状态。将使用COX回归模型来计算调整后的风险比。我们完善的、具有特点的队列，加上随时可以获得的数据和组织，为研究这些问题提供了一个独特且具有成本效益的机会，预期积极的结果将提供：1)其他方法，用来识别患有BE的高危受试者，以便进行更频繁的监测；以及2)短期干预研究的可修改因素。

DESCRIPTION (provided by applicant): Insulin-like growth factors (IGFs) are potent mitogens that play pivotal roles in regulation of cell proliferation, differentiation and apoptosis. IGFs implement their role through interactions with several molecules, including IGF-1 receptors on the cell membrane (in particular, IGF-1R) and several IGF binding proteins (notably IGFBP-3). In addition, polymorphisms in IGF-1, IGF-1R and IGFBP-3 genes have been identified that may have functional significance with regard to tissue concentrations of IGFs. Increased serum concentrations of IGFs, along with decreased concentrations of IGFBP-3, recently have been reported to increase risk of several cancers. We propose to take advantage of data and specimens collected in an ongoing cohort study of predictors of neoplastic progression in persons with Barrett's esophagus (BE) (n = 420, up to 8 years of follow up) to determine whether IGFs are related to risk of esophageal adenocarcinoma (EA), and a series of biomarkers validated as predictors of EA. The subjects donated blood and underwent endoscopic biopsies, physical examination and interview at baseline. Regular follow-up endoscopies and biopsies have been performed since baseline. Aim 1 will determine whether increased baseline serum levels of IGF-1 and decreased levels of IGFBP-3 are associated with increased risk of neoplastic progression in BE. Neoplastic progression will be determined by the development of EA, high-grade dysplasia, increased 4N/G2 fractions, aneuploidy and/or 17pLOH. Aim 2 will determine whether polymorphisms in IGF-1, IGF-1 receptor and IGFBP-3 genes are related to risk of neoplastic progression, and whether they modify any associations observed in the first aim. Secondary aims will investigate whether observed IGF associations are modified by key risk factors for EA and BE, including obesity, waist:hip ratio, and use of NSAIDs, serum selenium and menopausal status. Cox regression models will be used to calculate adjusted hazard ratios. Our well-established and characterized cohort, together with data and tissue that are readily available, afford a unique and cost-efficient opportunity to study these issues, with the expectation that positive results would provide i) additional methods with which to identify high risk subjects with BE for more frequent surveillance, and ii) modifiable factors for short-term intervention studies.