Systematic Functional Characterization of RNA Editing in Endometrial Cancer

描述（由申请人提供）：子宫内膜癌是美国最常见的妇科癌症。对这种疾病的研究主要集中在识别关键的遗传畸变，如体细胞突变，但尚未建立有效的靶向治疗方法。相比之下，由RNA编辑（一种重要的表观遗传控制）引起的RNA水平上的“突变”，在子宫内膜癌乃至一般癌症中很少受到关注。迄今为止，个别RNA编辑事件的重要性已在几种癌症类型中得到证实；然而，尚未对任何类型的癌症进行全面的调查。引人注目的是，本研究小组的初步分析显示，主要RNA编辑酶的过表达与子宫内膜癌患者的低生存率显著相关。长期目标是阐明RNA编辑在子宫内膜癌病理生理中的作用，并开发新的生物标志物或治疗策略。目前的目标是系统地识别“驱动”RNA编辑事件并阐明它们

DESCRIPTION (provided by applicant): Endometrial cancer is the most common gynecological cancer in the United States. Research efforts in this disease have focused on identifying key genetic aberrations such as somatic mutations, but no effective targeted therapies have been established. By contrast, "mutations" at the RNA level caused by RNA editing, an important epigenetic control, have received little attention in endometrial cancer and indeed, cancer in general. To date, the importance of individual RNA editing events has been documented in several cancer types; however a comprehensive investigation has not been attempted in any cancer type. Strikingly, the preliminary analyses by this research team reveal that the overexpression of major RNA editing enzymes significantly correlates with poor patient survival in endometrial cancer. The long-term goal is to elucidate the role of RNA editing in the pathophysiology of endometrial cancer and develop novel biomarkers or treatment strategies. The current objective is to systematically identify "driver" RNA editing events and elucidate their associated mechanisms in this disease. The central hypothesis is that some RNA editing events play a crucial role in the initiation and progression of endometrial tumors. The rationale is that the key RNA-editing-induced nucleotide changes identified will represent promising biomarkers or therapeutic targets for endometrial cancer and such a study will have major impacts across the breadth of oncology. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: Aim 1. Detect RNA editing sites associated with tumor over-editing activity or clinical variables in endometrial cancer. The Cancer Genome Atlas (TCGA) sequencing data will be analyzed to identify RNA editing sites that have significant over-editing activity in endometrial tumors or correlate with important clinical variables. The observed patterns of RNA editing will then be validated using orthogonal approaches in both TCGA samples and a large, independent, in-house cohort of endometrial tumor samples. The preliminary results have demonstrated a substantial number of such RNA editing sites. Aim 2. Identify driver RNA editing events in the pathogenesis of endometrial tumors. The functional impact of RNA editing events identified in Aim 1 will be examined through a novel two-step functional assessment strategy using highly sensitive cell viability assays. The genomic aberrations associated with these editing events will be determined through disequilibrium analyses on TCGA/in-house genomics data. For the RNA editing driver events, functional proteomics in selected endometrial tumor cell lines will be used to identify their affected signaling pathways. This project is innovative because it represents a systematic approach to identifying key epigenetic changes as the molecular basis of endometrial cancer. It is significant because the knowledge gained will vertically advance the understanding of endometrial tumorigenesis and facilitate the development and implementation of a novel class of biomarkers or therapeutic targets. In addition, the computational and experimental methods established will be readily applicable to other cancer types.