Molecular Classification of Endometrial Carcinomas

描述(申请人提供)：子宫内膜癌(EC)是一种高度异质性的疾病实体，由不同的组织病理学和临床特征定义的至少两个类别组成。除了传统上定义的I型(与高雌激素症有关，低级别子宫内膜样组织学，预后良好)和II型(没有明确的流行病学危险因素，高级别乳头状浆液或透明细胞组织，预后差)外，还可能存在第三类定义不明确的肿瘤，包括高结构或核级别的子宫内膜样瘤，预后中等至差。通常很难根据这些一般类别中的一个或另一个对食典性结肠炎的个别病例进行分类。临床结果的这种异质性可能反映了单个癌症潜在的分子遗传学特征的差异，但EC的分子遗传学基础在很大程度上仍然不清楚。因此，这个项目的长期目标是解决这样的假设，即全面的EC分子遗传学分类将提高我们对EC个体病例进行分类并预测治疗和临床结果的能力。此外，阐明这些临床结果参数的分子决定因素将为子宫内膜肿瘤发生的生物学基础提供实质性的见解，并为EC治疗提供潜在的新靶点或策略。我们认为，这一目标可以通过系统地应用新的、全面的分子筛查方法来实现，特别是使用微阵列进行全基因组基因表达分析，以及与广泛的外科、组织病理学和临床数据相联系的大型EC组织资源。该项目的具体目标是：1)使用寡核苷酸表达阵列获得大量EC的RNA表达谱，以确定由表达特征组装的亚群；2)通过将这些分子观察与临床结果和病理状态相关联，定义预测治疗反应和生存的EC的不同分子亚集；以及3)使用靶向分析和组织方法确认和完善特定目标1和2的观察结果。

DESCRIPTION (provided by applicant): Endometrial carcinoma (EC) is a highly heterogeneous disease entity, consisting of at least two categories defined by distinct histopathological and clinical features. In addition to the traditionally defined type I (association with hyperestrogenism, low grade endometrioid histology, and good prognosis) and type II (no well defined epidemiologic risk factors, high grade papillary serous or clear cell histologies, and poor prognosis) tumors, there may also exist a poorly defined third category, consisting of endometrioid tumors of high architectural or nuclear grade and moderate to poor prognosis. Often it is difficult to classify an individual case of EC with respect to one or another of these general categories. This heterogeneity in clinical outcome presumably reflects differences in the underlying molecular genetic characteristics of individual cancers, but the molecular genetic basis of EC remains largely obscure. Thus, the long term goal of this project is to address the hypothesis that a comprehensive molecular genetic classification of EC will improve our ability to classify individual cases of EC and predict response to therapy and clinical outcome. Furthermore, elucidation of the molecular determinants of these clinical outcome parameters should provide substantial insights into the biological basis of endometrial tumorigenesis, as well as suggest potential new targets or strategies for EC therapy. We propose that this goal may be accomplished through the systematic application of new, comprehensive molecular screening methodologies, specifically, the use of microarrays for genome-wide gene expression analyses, together with a large EC tissue resource linked to extensive surgical, histopathological, and clinical data. The specific aims of this project are to: 1) obtain RNA expression profiles of a large number of ECs using oligonucleotide expression arrays to identify subgroups assembled by expression characteristics; 2) define distinct molecular subsets of EC that will predict response to therapy and survival, by correlating these molecular observations with clinical outcomes and pathological states; and 3) confirm and refine observations from specific aims one and two using targeted assays and tissue-based approaches.