High-throughput Epigenomic Mapping of Regulatory Elements in Ovarian Cancer at Basepair Resolution

项目总结/摘要 OC是美国最致命的妇科癌症。它由几种组织型组成，每种组织型在生物学上都不同 不同的临床挑战。在父母补助金发放的头三年半里，尽管面临挑战， 在新冠疫情的影响下，我们能够在完成所有目标方面取得重大进展。我们有 发表或提交了四篇论文，还有三篇即将提交。我们能够开发新的 新技术、新的生物信息学工具，按计划生成和分析表观基因组和转录组数据。 特别是，我们发现透明细胞卵巢癌（CCOC）和类卵巢癌（ENOC）， 两种密切相关的OC组织型，类似于不同月经周期阶段的正常子宫内膜细胞 （增殖/卵泡，分泌/黄体）。传统上，起源细胞和累积的基因突变是 被认为是癌症发生和发展中最重要的决定因素。然而，这一教条 不适用于CCOC和ENOC的情况，因为这两种卵巢癌亚型都是由同一种细胞引起的。 起源（异位子宫内膜/子宫内膜样细胞），并共享共同的基因突变（ARID 1A，PIK 3CA， KRAS），但在细胞表型和临床行为上表现出显著差异。通过案件的 ENOC和CCOC，我们能够表明细胞状态（与细胞类型相对）是一个被低估的概念 在讨论细胞的起源，以及如何非遗传机制（表观遗传和转录）调节这一点， 过程我们还观察到显微切割的肿瘤区室中存在大量的分子异质性， 特别是高级别浆液性卵巢癌（HGSOC），表明存在显著的肿瘤内 在原发性人类肿瘤中的细胞异质性，这是一个父母资助不能充分解决的问题。因此，我们认为， 我们建议检查原代人OC细胞状态的非表观遗传调节因子的单细胞变异 样品，与新技术开发期间，母公司赠款。

PROJECT SUMMARY / ABSTRACT OC is the deadliest gynecological cancer in the US. It consists of several histotypes, each biologically distinct with different clinical challenges. In the first three and half years of the parent grant, in spite of challenges imposed by COVID, we were able to make substantial progress towards completion of all Aims. We have published or submitted four papers, with three more to be submitted soon. We were able to develop novel technologies, new bioinformatics tools, generate and analyze epigenomic and transcriptomic data as planned. In particular, we discovered that clear cell ovarian cancer (CCOC) and endometrioid ovarian cancer (ENOC), two closely related OC histotypes, resemble normal endometrial cells at different menstrual cycle phases (proliferative/follicular, secretory/luteal). Traditionally, the cell-of-origin and accumulated genetic mutations are viewed as the most important determinants in initiation and development of cancer. However, this dogma does not apply to the case of CCOC and ENOC, in that both ovarian cancer subtypes arise from the same cell-of- origin (ectopic endometrium/endometrial-like cells) and share common genetic mutations (ARID1A, PIK3CA, KRAS), yet demonstrate drastic differences in cellular phenotype and clinical behavior. Through the case of ENOC and CCOC, we were able to show how cell state (as opposed to cell type) is an underappreciated notion in the discussion of cell of origin, and how non-genetic mechanisms (epigenetic and transcriptional) regulate this process. We also observed substantial molecular heterogeneity in the microdissected tumor compartment, particularly high-grade serous ovarian cancer (HGSOC), suggesting the presence of significant intratumoral cellular heterogeneity in primary human tumors, an issue the parent grant cannot sufficiently address. Therefore, we propose to examine single-cell variations of non-epigenetic regulators of cellular states in primary human OC samples, with novel technologies developed during the parent grant.