The USC-JHU Cancer Epigenome Characterization Center

描述（由申请人提供）：在过去的二十年中，已经清楚的是，癌症不仅是由于遗传事件（如突变、拷贝数改变和序列重排）引起的，而且也是表观基因组广泛变化的结果。表观遗传学改变导致癌症的起源和恶性进展，并影响临床结果。USC-JHU癌症表观基因组表征中心专门从事基因组规模癌症表观遗传数据的生产和分析。在癌症基因组图谱的试点阶段，我们的中心一直负责TCGA内所有高通量表观基因组数据的生产和沉积。TCGA试验的一个关键结果是我们发现多形性胶质母细胞瘤中MGMT启动子甲基化、烷化剂治疗和与错配修复缺陷相关的超变子表型之间存在联系，这一观察结果具有潜在的临床意义。对于TCGA的下一阶段，我们提出以下三个目标。目的1是使用Illumina Infinium DNA甲基化分析平台，表征至少10，000份人类癌症样本和1，000份对照样本中位于14，495个基因启动子中的27，578个CpG二核苷酸的DNA甲基化状态。目的2是将TCGA中的表观基因组数据生产过渡到全基因组鸟枪亚硫酸氢盐序列分析，以提供TCGA癌症样本的单碱基对分辨率DNA甲基化数据。目标3是实施质量控制和质量保证措施，以确保为公开传播而保存的表观基因组数据符合严格的标准。我们的团队在癌症表观基因组学方面拥有相当丰富的专业知识，其中有两位癌症表观遗传学领域的创始人，他们共同开创了大多数广泛使用的DNA甲基化分析技术，并提供了许多生物学见解。表观基因组数据是充分理解癌症基因组改变与个体肿瘤起源和临床多样性之间关系的必要组成部分。

DESCRIPTION (provided by applicant): In the past two decades, it has become clear that cancer arises not only as a consequence of genetic events, such as mutations, copy number alterations, and sequence rearrangements, but also as a result of extensive changes to the epigenome. Epigenetic alterations contribute causally to the origin and malignant progression of cancer, and affect clinical outcome. The USC-JHU Cancer Epigenome Characterization Center specializes in the production and analysis of genome-scale cancer epigenetic data. During the pilot phase of The Cancer Genome Atlas, our center has been responsible for the production and deposition of all high-throughput epigenomic data within TCGA. A key outcome of the TCGA pilot was our finding of a link in glioblastoma multiforme between MGMT promoter methylation, treatment with alkylating agents, and a hypermutator phenotype associated with mismatch repair deficiency, an observation with potential clinical implications. For the next phase of TCGA, we propose the following three objectives. Objective 1 is to characterize the DNA methylation status of 27,578 CpG dinucleotides located in 14,495 gene promoters in at least 10,000 human cancer samples and 1,000 control samples using the lllumina Infinium DNA Methylation analysis platform. Objective 2 is to transition epigenomic data production in TCGA to whole genome shotgun bisulfite sequence analysis to provide single-base-pair resolution DNA methylation data for TCGA cancer samples. Objective 3 is to implement quality control and quality assurance measures to ensure that epigenomic data deposited for public dissemination meets rigorous standards. Our group has considerable expertise in cancer epigenomics, with two founders of the field of cancer epigenetics and with members who collectively have pioneered the majority of widely used DNA methylation analysis techniques, and who have provided many of the biological insights. Epigenomic data are a necessary component for a full understanding of the relationship between alterations in the cancer genome and the origin and clinical diversity of individual tumors.