Biomarkers for Esophageal Cancer Progression and Prognosis

描述(申请人提供)：食道癌发生在两种主要的组织学类型：鳞状细胞癌(SCC)和腺癌(EA)，这两种类型的预后都非常差。虽然这些肿瘤通常被作为一种疾病来治疗，但它们在流行病学、危险因素和生物学行为上都有明显的差异。在西化国家，鳞癌的发病率在过去的25年里一直在稳步下降，而EA的发病率一直在急剧上升(~400%)。事实上，EA现在是美国所有肿瘤中发病率上升速度最快的。这很可能与肥胖率上升和胃食道反流病的高患病率有关，据估计，胃食道反流病影响多达44%的美国人口，并与EA的发展密切相关。尽管有所上升，但由于每年的病例数量相对较低，以及单一机构无法获得大量患者队列进行研究，食管腺癌的研究变得困难。因此，与更常见的肿瘤类型相比，人们对这种疾病的生物学了解要少得多。在全基因组范围内，人们对EA特有的遗传异常和基因表达变化知之甚少。部分由于我们所知的这些不足，目前几乎没有用于疾病诊断、进展或预后的生物标志物，也没有指示用于治疗这种高度致命的肿瘤的靶向治疗药物。我们的研究小组在解决这些不足方面处于有利地位，因为我们有一个专注于转译研究的多学科团队，我们正在进行的、由R01资助的研究使我们能够开发具有所有患者详细临床信息的大型组织库。在这项提案中，我们打算利用这些资源来生成分子分期工具，并确定新的治疗靶点，以改善食管腺癌患者的治疗。具体地说，我们建议使用高密度DNA阵列来检查EA的基因组，以便识别在这种肿瘤类型中经常改变的基因组区域。然后，我们将识别这些改变区域内的所有基因，并从Affymetrix U133阵列中提取它们的表达水平。其表达水平与DNA拷贝数变化相关的基因将与“可药物”靶标数据库进行交叉参考，以确定食管腺癌潜在的新治疗靶点。我们还将确定哪些区域和基因与疾病分期、转移和生存相关。这些区域及其内部基因的表达与临床终点的关联将在一个独立的肿瘤集中使用定量聚合酶链式反应进行验证。最后，结合经过验证的预后标志物，开发出一种分子分期算法，用于指导食管腺癌患者的治疗。因此，在本研究结束时，我们将识别、验证和验证可用于食管腺癌诊断、分期和治疗的新的遗传标记。公共卫生相关性：食管腺癌的增长速度比任何其他恶性肿瘤都快，通常诊断较晚，预后较差。尽管在高通量基因组分析方法方面取得了重大进展，但在全基因组DNA改变的水平上，这种疾病仍然很大程度上没有被研究。识别特定的DNA改变及其基因，可以为食管腺癌的诊断、进展和预后提供标志物，并为食管腺癌的治疗发现和治疗提供新的靶点。

DESCRIPTION (provided by applicant): Esophageal cancer occurs in two major histologic types; squamous cell carcinoma (SCC) and adenocarcinoma (EA) both of which have an extremely poor prognosis. Although these tumors are often treated as one disease, they have distinct differences in epidemiology, risk factors and biological behavior. In Westernized countries the incidence of SCC has been steadily decreasing over the past 25 years, while EA rates have been increasing dramatically (~400%). In fact, EA now has the fastest rate of increased incidence of any tumor in the United States. This is most likely linked to the rise in obesity and the high prevalence of gastroesophageal reflux disease, which is estimated to affect up to 44% of the American population and is strongly linked to the development of EA. Despite this rise, research on esophageal adenocarcinoma is made difficult by the relatively low number of cases per year and the inability of single institutions to acquire large patient cohorts for study. Consequently much less is known about the biology of this disease than about more prevalent tumor types. On a genome-wide scale, very little is known about the genetic aberrations and gene expression alterations that are specific to EA. Partly as a result of these deficiencies in our knowledge, there are currently very few biomarkers for disease diagnosis, progression or prognosis and there are no targeted therapeutic agents indicated for the treatment of this highly lethal tumor. Our research group is in a strong position to address these deficiencies since we have a multi-disciplinary team focused on translational research and our ongoing, R01-funded studies have enabled us to develop large tissue banks with detailed clinical information on all patients. In this proposal, we intend to utilize these resources in order to generate molecular staging tools and to identify novel therapeutic targets to improve the treatment of esophageal adenocarcinoma patients. Specifically, we propose to examine the genome of EA using high density DNA arrays in order to identify genomic regions that are frequently altered in this tumor type. We will then identify all genes within these altered regions and extract their expression levels from Affymetrix U133 arrays. Genes whose expression levels correlate with DNA copy number change will be cross-referenced against "druggable" target databases in order to identify potential new therapeutic targets for esophageal adenocarcinoma. We will also determine which of the regions and genes are associated with disease stage, metastasis and survival. The association of these regions and the expression of genes within them with clinical endpoints will then be validated in an independent tumor set using quantitative PCR. Finally, validated prognostic markers will be combined to develop a molecular staging algorithm that can be used to guide therapy for esophageal adenocarcinoma patients. Thus, at the end of this study we will have identified, verified and validated novel genetic markers that could be used for diagnosis, staging and treatment of esophageal adenocarcinoma. PUBLIC HEALTH RELEVANCE: Esophageal adenocarcinoma is increasing faster than any other malignancy and typically has a late diagnosis and poor outcome. Despite major advances in high-throughput genomic analysis methods, this disease remains largely unstudied at the level of genome-wide DNA alterations. The identification of specific DNA alterations and the genes within them could lead to markers for diagnosis, progression and prognosis as well as providing novel targets for therapeutic discovery and treatment of esophageal adenocarcinoma.