Cancer Genetics and Epigenetics

项目摘要/摘要 埃默里大学温希普癌症研究所的癌症遗传学和表观遗传学(CGE)项目是 以实验室为基础的基础科学计划，旨在更好地了解基因和表观遗传如何改变 基因组的组成部分对人类癌症的发生和发展做出了贡献。在领导下 保拉·维蒂诺博士(领队)和董进堂博士(联合领队)CGE计划包括27个核心 成员来自埃默里大学的14个系和3所学院，包括 医学院、埃默里学院和罗林斯公共卫生学院。CGE计划的目标是更好地 了解维持基因组稳定性和适当的基因调控的机制 网络，这些如何在癌细胞中被破坏，以及它们的破坏如何有助于启动和 癌症的进展。CGE计划旨在促进基因组技术的扩大应用 在癌症表型和结果的分子分类中。该计划的科学重点是 围绕三个相互关联和相辅相成的主题组织：(1)DNA损伤、修复和细胞 对压力的反应，(2)表观遗传学和基因调控，(3)癌症遗传学和基因组学。超过了 在上一个竞争周期，CGE计划成员发表了256篇与癌症相关的科学文章。的 其中55个(21%)是计划内协作，105个(41%)是计划间协作，123个(48%) 代表与另一个癌症中心或其他学术组织的合作。截至2016年3月31日， CGE每年持有910万美元的癌症相关研究资金，其中约300万美元 (33%)由NCI颁发。强大的科学协同效应导致了重大发现。关键见解 探讨DNA双链断裂修复的机制，复制应激是如何化解的，以及辐射 突变是化疗和辐射反应的重要预测因子。地标 对Tet双加氧酶的结构和功能的研究揭示了氧化 甲基胞嘧啶残留物不仅是周转率为5mC的瞬时中间体，而且是一种独特的成分 控制基因表达程序的表观遗传‘密码’。已经取得了巨大的进步，朝着 成功地翻译了该计划的遗传学/基因组学工作，包括对 关键的驱动因素基因突变和这种改变揭示的独特的细胞脆弱性，一种基于RNA的 用于侵袭性前列腺癌早期检测的生物标记物小组，一种联合的RNA-DNA风险测试 口咽癌的分层和临床基因组学工作流程的实施 在几种癌症类型中的决策。总体而言，CGE计划促进中心范围内的目标 通过确定癌细胞的关键点改善佐治亚州的癌症预后 可利用的脆弱性，可用于新的治疗机会和基因组和 表观基因组特征作为临床结果和人群风险的预测因子。

PROJECT SUMMARY/ABSTRACT The Cancer Genetics and Epigenetics (CGE) Program of Winship Cancer Institute of Emory University is a laboratory-based basic science program that seeks to better understand how altered genetic and epigenetic components of the genome contribute to the initiation and progression of human cancers. Under the leadership of Paula Vertino, PhD (leader) and Jin-Tang Dong, PhD (co-leader) the CGE Program includes 27 core members drawn from 14 departments and three schools across Emory University, including the School of Medicine, Emory College, and Rollins School of Public Health. The goals of the CGE program are to better understand the mechanisms that govern the maintenance of genome stability and proper gene regulatory networks, how these become corrupted in cancer cells, and how their disruption contributes to the initiation and progression of cancer. The CGE Program seeks to promote the expanded application of genomic technologies in the molecular classification of cancer phenotypes and outcomes. The scientific focus of the program is organized around three inter-related and complimentary themes: (1) DNA Damage, Repair, and Cellular Responses to Stress, (2) Epigenetics and Gene Regulation, and (3) Cancer Genetics and Genomics. Over the last competitive cycle CGE Program members have published 256 cancer-relevant scientific articles. Of these, 55 (21%) were intra- and 105 (41%) were inter-programmatic collaborations, and 123 (48%) represented a collaboration with another cancer center or other academic organization. As of March 31, 2016, CGE held $9.1 million in annual total cancer-relevant research funding, of which approximately $3 million (33%) was awarded from the NCI. Strong scientific synergism has led to important discoveries. Key insights into the mechanism of DNA double strand break repair, how replication stress is resolved, and radiation mutagenesis are leading to important predictors of chemotherapy and radiation response. Landmark investigations into the structure and function of the TET dioxygenase enzymes have revealed oxidized methylcytosine residues to be more than a transient intermediate in the turnover of 5mC, but a distinct component of the epigenetic ‘code’ governing gene expression programs. Significant strides have been taken towards the successful translation of the program’s genetics/genomics efforts, including new insight into the contribution of key ‘driver’ gene mutations and the unique cellular vulnerabilities that such alterations unmask, an RNA-based biomarker panel for the early detection of aggressive prostate cancer, a combined RNA-DNA test for risk stratification in oropharyngeal carcinomas, and the implementation of a clinical genomics workflow to guide decision making in several cancer types. Overall, the CGE Program promotes center-wide goals for improvements in cancer outcomes across the state of Georgia by identifying of key points of cancer cell vulnerability that can be exploited towards new therapeutic opportunities and the development of genomic and epigenomic signatures as predictors of clinical outcomes and population risk.