Biomarkers for Esophageal Cancer Progression and Prognosis

描述（由申请人提供）：食管癌有两种主要的组织学类型：鳞状细胞癌（SCC）和腺癌（EA），两者的预后都极差。虽然这些肿瘤通常被视为一种疾病，但它们在流行病学，危险因素和生物学行为方面存在明显差异。在西方国家，SCC的发病率在过去的25年中一直在稳步下降，而EA的发病率却在急剧上升（~400%）。事实上，EA现在是美国任何肿瘤发病率增长最快的。这很可能与肥胖症的增加和胃食管反流病的高患病率有关，据估计，胃食管反流病影响高达44%的美国人口，并与EA的发展密切相关。尽管这种上升，食管腺癌的研究是困难的，因为每年的病例数相对较低，单一机构无法获得大量的患者队列进行研究。因此，对这种疾病的生物学了解要比对更普遍的肿瘤类型了解少得多。在全基因组范围内，很少有人知道的遗传畸变和基因表达的改变是特定于EA。部分由于我们知识中的这些缺陷，目前用于疾病诊断、进展或预后的生物标志物非常少，并且没有靶向治疗剂指示用于治疗这种高致死性肿瘤。我们的研究小组在解决这些缺陷方面处于有利地位，因为我们有一个专注于转化研究的多学科团队，并且我们正在进行的R 01资助的研究使我们能够开发大型组织库，其中包含所有患者的详细临床信息。在这项提案中，我们打算利用这些资源，以产生分子分期工具，并确定新的治疗靶点，以改善食管腺癌患者的治疗。具体来说，我们建议使用高密度DNA阵列检查EA的基因组，以确定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Affytron 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“可用药”靶点数据库交叉引用，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阶段，转移和生存相关。这些区域和其中基因表达与临床终点的关联随后将使用定量PCR在独立肿瘤组中进行验证。最后，将结合经验证的预后标志物来开发可用于指导食管腺癌患者治疗的分子分期算法。因此，在本研究结束时，我们将确定，验证和验证新的遗传标记，可用于诊断，分期和治疗食管腺癌。公共卫生相关性：食管腺癌的发病率比任何其他恶性肿瘤都要快，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，但这种疾病在全基因组DNA改变的水平上仍然没有得到很大程度的研究。特异性DNA改变及其基因的鉴定可以为食管腺癌的诊断、进展和预后提供标志物，并为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.