Tools for detecting biologically important sequence variation in cancer

描述（由申请人提供）：检测生物学上重要的序列变异是现代癌症基因组学的主要目标。为了将重测序研究集中在高价值区域，许多研究人员选择专注于外显子组（蛋白质编码外显子），这有望丰富功能变异。在不久的将来，对个体外显子组进行全面重测序的成本可能低于1000美元，大大低于全基因组测序。我们预计，这些进展将在癌症基因组中产生大量的外显子序列变异，这将为新的癌症基因和药物靶点提供线索。大多数这种变异可能是有效的中性，因此癌症基因组学社区将不得不识别和优先考虑那些需要在测定系统中进一步研究的变异，例如细胞系和模式生物。在这个时候，没有公开可用的资源，使研究人员谁不是生物信息学专家，以探索在他们的调查中发现的序列变异的生物重要性。迫切需要一种工具，通过将变异映射到蛋白质和通路上，并以普通研究人员可以访问的方式呈现结果，从而实现透明的、研究人员驱动的变异探索。这些资源的开发将使基因组研究能够迅速转化为医学研究的实际进展。我们建议在这里开发一种新的计算应用程序，以满足正在发现癌症外显子组变异的研究人员的需求。我们的工作将产生一个高通量的注释管道，与相关的基于Web的分析和可视化工具。该资源将使用户能够解释和优先考虑肿瘤衍生的序列变化，并帮助他们考虑如何为感兴趣的变体设计功能测试。我们将通过与约翰霍普金斯西德尼·金梅尔癌症研究中心的研究人员合作来证明该应用程序的实用性，他们在我们申请资助的两年期间对11种癌症类型的外显子组进行测序（每种癌症类型约23种原发性肿瘤）。该应用程序将与由Bert Vogelstein，Ken Kinzler和维克托Velculescu博士领导的研究小组合作，以确定负责这些癌症易感性和进展的基因（随附支持信）。这项工作将为这些工具在其他癌症中的外显子组变异数据的更广泛应用奠定基础，例如NCI的癌症基因组图谱项目和TARGET正在研究的那些。 公共卫生相关性：我们建议开发软件工具，使基因组学研究人员能够分析人类外显子组中的序列变异，以改善诊断，预后和针对癌症的药物开发。在该项目的试点阶段，我们将使用这些工具来识别变体、基因和相关基因组，这些基因是约翰霍普金斯西德尼·金梅尔癌症中心正在测序的11种癌症类型的易感性和进展的基础。

DESCRIPTION (provided by applicant): The detection of biologically important sequence variation is a major goal of modern cancer genomics. In an effort to focus resequencing investigations on high-value regions, many researchers have chosen to focus on the exome (protein-coding exons), which is expected to be enriched for functional variation. In the near future, comprehensive resequencing of an individual's exome may cost less than $1000, substantially less than whole-genome sequencing. We anticipate that these developments will yield an enormous amount of exonic sequence variation in cancer genomes that will provide leads to new cancer genes and drug targets. Most of this variation is likely to be effectively neutral, thus the cancer genomics community will have to identify and prioritize those variants that warrant further studies in assay systems, e.g. cell lines and model organisms. At this time, there are no publicly available resources that enable researchers who are not bioinformatics experts to explore the biological importance of sequence variants discovered in their investigations. There is a pressing need for tools that enable transparent, researcher-driven exploration of variation, by mapping variants onto proteins and pathways and presenting results in a way that is accessible to the average researcher. Development of such resources will allow rapid translation of genomic investigations into tangible progress in medical research. We propose here to develop a novel computational application tailored to the needs of researchers who are discovering variation in the exomes of cancers. Our work will produce a high- throughput annotation pipeline, with associated web-based analysis and visualization tools. This resource will enable users to interpret and prioritize tumor-derived sequence changes and help them think about how to design functional tests for variants of interest. We will demonstrate the utility of the application by collaborating with researchers from the Johns Hopkins Sidney Kimmel Cancer Research Center, who are sequencing the exomes of eleven cancer types during the two years for which we request funding (approximately 23 primary tumors per cancer type). The application will be used in collaboration with this team of researchers, led by Drs. Bert Vogelstein, Ken Kinzler, and Victor Velculescu to identify genes responsible for susceptibility to and progression of these cancers (Support Letter attached). This work will lay the foundation for a broader application of the tools to exomic variation data in additional cancers, such as those being studied by NCI's Cancer Genome Atlas project and TARGET. PUBLIC HEALTH RELEVANCE: We propose to develop software tools that will enable genomics researchers to analyze sequence variation in the human exome, for the purpose of improving diagnosis, prognosis and drug development targeted at cancers. In the pilot stage of the project, we will use the tools to identify variants, genes, and groups of related genes that underlie susceptibility to and progress of eleven cancer types being sequenced at Johns Hopkins' Sidney Kimmel Cancer Center.