Functional Annotation of Cancer Genomes: TCGA, Glioblastoma and Ovarian Cancer

描述（由申请人提供）：大多数人类肿瘤，特别是源自上皮癌的肿瘤，表现出全局基因组改变，使得难以识别对细胞转化至关重要的突变，并难以定义特定癌症相关突变的后果。测序技术和绘制癌症相关扩增子和缺失的综合方法的最新进展现在使识别特定肿瘤所包含的所有遗传改变成为可能，并且大规模的努力，如TCGA，应用这些技术已经开始提供癌症基因组的全面视图。 尽管取得了这些重要进展，但将这些发现转化为将进入临床的疗法的关键瓶颈仍然是作为潜在治疗靶点的基因的功能表征（感兴趣的遗传元件，GEOI）。具体而言，虽然在相当大一部分特定癌症类型中突变的基因的鉴定是必不可少的第一步，但同时开发有效的方法来注释癌症相关基因的功能对于从癌症基因组的结构描述中提取有希望的候选癌症靶标是必要的。因此，癌症基因的功能注释将识别其蛋白质产物对肿瘤起始或维持至关重要的那些基因，并将提供对这些相同癌症中失调的生化途径的关键见解。这些信息将加速新的分子靶向治疗的发展。 我们最近开发了必要的方法和工具，采取综合方法，将癌症基因组的高通量功能表征与正在进行的基因组表征工作的新兴知识相结合。在本申请中，我们提出了一种集成管道，其（1）将联合收割机组合全基因组功能丧失和功能获得方法，以揭示候选癌症基因功能与由TCGA导出的关于在脑（GBM）和卵巢（OVCA）癌症中发现的遗传改变的信息，和（2）将无限制地向癌症研究团体提供该信息和试剂。通过这些研究获得的信息将促进由药物引发的基础和转化研究，并加速新治疗方法的开发。鉴于与这些疾病相关的不良预后，我们预计该计划的影响将是重大和及时的。此外，该计划可以在2年内执行，并需要额外的人员来完成。因此，该计划符合NIH挑战赠款计划和2009年美国复苏和再投资法案的目标。虽然专注于GBM和OVCA，但该项目将为癌症基因组的广泛功能注释提供基础。 公共卫生相关性：这些研究的首要目标是实施高通量技术，为胶质母细胞瘤和卵巢癌中突变或扩增的基因提供功能信息，并将这些信息和经验证的试剂传播给癌症研究界。使用这些方法鉴定的癌症基因代表了癌症研究者发起的研究计划的优先候选者，以及对未来治疗工作特别有希望的目标。这些研究将利用先前在癌症基因组表征方面的投资，并提供将促进癌症研究者发起的基础和转化研究的产出，并加速新治疗方法的开发。

DESCRIPTION (provided by applicant): Most human tumors, particularly those derived from epithelial cancers, exhibit global genomic alterations that make it difficult to identify mutations critical for cell transformation and to define the consequences of specific cancer-associated mutations. Recent advances in sequencing technologies and comprehensive methods to map cancer-associated amplicons and deletions now make it possible to identify all of the genetic alterations harbored by a particular tumor, and large-scale efforts such as TCGA to apply these technologies have already begun to provide comprehensive views of cancer genomes. Despite these important advances, a critical bottleneck in translating these discoveries into therapies that will enter the clinic remains the functional characterization of genes as potential therapeutic targets (genetic elements of interest, GEOI). Specifically, although the identification of genes that are mutated in a substantial fraction of particular cancer types is an essential first step, the parallel development of efficient methods to annotate the function of cancer-associated genes is necessary to distill promising candidate cancer targets from this structural description of cancer genomes. Thus, functional annotation of cancer genes will identify those genes whose protein products are essential for tumor initiation or maintenance and will provide critical insights into the biochemical pathways that are dysregulated in these same cancers. This information will accelerate the development of new molecularly targeted therapeutics. We have recently developed the methods and tools necessary to take an integrated approach that combines the high throughput functional characterization of cancer genomes with the emerging knowledge from on-going genome characterization efforts. In this application, we propose an integrated pipeline that (1) will combine a whole genome loss-of-function and gain- of-function approaches to uncover candidate cancer gene function with the information derived by TCGA on genetic alterations found in brain (GBM) and ovarian (OVCA) cancer and (2) will provide this information and reagents to the cancer research community without restrictions. The information obtained by these studies will facilitate investigator-initiated basic and translational studies and accelerate the development of new therapeutic approaches. Given the poor prognosis associated with these diseases, we anticipate that impact of this program will be both major and timely. Moreover, this program can be executed within 2 years and will require additional personnel to complete. As such, this program is consistent with the goals of the NIH Challenge Grant Program and the American Recovery and Reinvestment Act of 2009. Although focused on GBM and OVCA, this project will provide a foundation for the broad functional annotation of cancer genomes. PUBLIC HEALTH RELEVANCE: The overarching goals of these studies are the implementation of high throughput technologies that will provide functional information for genes identified as mutated or amplified in glioblastoma and ovarian cancers and the dissemination of this information and validated reagents to the cancer research community. The cancer genes identified using these approaches represent prioritized candidates for investigator-initiated research programs and targets of particular promise for future therapeutic efforts. These studies will leverage prior investments in cancer genome characterization and provide outputs that will facilitate investigator-initiated basic and translational studies and accelerate the development of new therapeutic approaches.