The USC-JHU Cancer Epigenome Characterization Center

描述(申请人提供)：在过去的二十年里，癌症的发生不仅是基因事件的结果，如突变、拷贝数改变和序列重排，而且也是表观基因组广泛变化的结果。表观遗传改变是癌症发生和恶性进展的原因，并影响临床预后。南加州大学-JHU癌症表观基因组特征中心专门生产和分析基因组规模的癌症表观遗传学数据。在癌症基因组图谱的试点阶段，我们的中心负责TCGA内所有高通量表观基因组数据的生产和存储。TCGA试验的一个关键结果是我们在多形性胶质母细胞瘤中发现了MGMT启动子甲基化、烷化剂治疗和错配修复缺陷相关的突变表型之间的联系，这一观察具有潜在的临床意义。对于下一阶段的TCGA，我们提出了以下三个目标。目的1利用LLUMINA Infinium DNA甲基化分析平台，分析至少10,000例人类肿瘤标本和1,000例对照标本中位于14,495个基因启动子的27,578个CpG二核苷酸的DNA甲基化状态。目标2是将TCGA的表观基因组数据生产过渡到全基因组鸟枪式亚硫酸盐序列分析，为TCGA癌样本提供单碱基分辨的DNA甲基化数据。目标3是实施质量控制和质量保证措施，以确保储存供公众传播的表观基因组数据符合严格标准。我们的团队在癌症表观遗传学领域拥有相当多的专业知识，拥有癌症表观遗传学领域的两位创始人和成员，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了解癌症基因组变化与单个肿瘤的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.