Modeling the impact of mutations in ubiquitin ligase genes on transcriptional programs in endometrial cancer

 描述（由申请人提供）：模拟泛素连接酶基因突变对子宫内膜癌转录程序的影响摘要：子宫内膜癌是美国最常见的妇科癌症，并一直是两个TCGA研究的主题，最近发表的子宫体子宫内膜癌（EC）和子宫癌细胞瘤（UC），一种罕见的和积极的亚型正在进行的研究。一项泛癌分析揭示了子宫癌中特异性泛素途径基因突变的惊人高频率：FBXW 7、SPOP和RNF 43，它们都编码不同E3泛素连接酶复合物中的底物识别蛋白，并且基于TCGA分析，在~44%的UC和~25%的EC中被体细胞突变改变。虽然这些基因在其他癌症中具有已知或提出的肿瘤抑制功能，但它们在子宫内膜癌中的研究很少。我们最近开发了一种新的计算方法，用于利用并行磷酸化蛋白质组学（反相蛋白质阵列）和mRNA表达（微阵列或RNA-seq）数据，通过TCGA将上游信号通路的失调与转录电路中的转录反应改变联系起来。重要的是，我们的方法为解释影响提供了一个统计原则框架 在转录因子和信号传导活性改变方面的突变和拷贝数事件。我们建议开发和应用我们的综合建模方法来解释频繁突变的泛素连接酶基因在子宫内膜癌中的作用。我们将追求一个主要的方法学的进步，在计算模型中，通过将详细的表观基因组信息从适当的细胞系模型，以代表转录因子结合信号增强。我们还将使用两种基因组相似的肿瘤类型（浆液性卵巢癌和浆液性子宫内膜癌）的比较建模，以潜在地将子宫内膜肿瘤中FBXW 7突变的较高频率与化疗耐药性联系起来。更广泛地说，这项工作将提供通用的方法学工具，使跨肿瘤类型的体细胞改变基因的其他类别的研究。

 DESCRIPTION (provided by applicant): Modeling the impact of mutations in ubiquitin ligase genes on transcriptional programs in endometrial cancer Abstract: Endometrial cancer is the most common gynecological cancer in the United States and has been the subject of two TCGA studies, a recently published characterization of uterine corpus endometrial carcinomas (ECs) and an ongoing study of uterine carcinosarcomas (UCs), a rare and aggressive subtype. A pan-cancer analysis reveals a strikingly high frequency of mutations of specific ubiquitin pathway genes in uterine cancers: FBXW7, SPOP, and RNF43, all encoding substrate recognition proteins in distinct E3 ubiquitin ligase complexes, and altered by somatic mutations in ~44% of UCs and ~25% of ECs based on TCGA analysis. While these genes have known or proposed tumor suppressor functions in other cancers, they are little studied in endometrial cancer. We have recently developed a novel computational approach for exploiting parallel phosphoproteomics (reverse-phase protein array) and mRNA expression (microarray or RNA-seq) data available for large tumor sets through TCGA to link dysregulation of upstream signaling pathways with altered transcriptional response through the transcriptional circuitry. Importantly, our approach provides a statistically principled framework for interpreting the impact of mutations and copy number events in terms of altered transcription factor and signaling activity. We propose to develop and apply our integrative modeling approach to interpret the role of frequently mutated ubiquitin ligase genes in endometrial cancer. We will pursue a major methodological advance in the computational model by incorporating detailed epigenomic information from appropriate cell line models in order to represent transcription factor binding signals in enhancers. We will also use comparative modeling of two genomically similar tumor types, serous ovarian and serous endometrial carcinomas, to potentially link the higher frequency of FBXW7 mutations in endometrial tumors to chemotherapeutic resistance. More broadly, this work will provide general methodological tools to enable the study of other classes of somatically altered genes across tumor types.