The joint WCM-NYGC Center for Functional and Clinical Interpretation of Tumor Profiles

WCM-NYGC 肿瘤特征功能和临床解读联合中心

基本信息

批准号：
9543442
负责人：
Olivier Elemento
金额：
$ 47.25万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-14 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9543442
关键词：
Automobile Driving Benchmarking CLIA certified Cancer Patient Clinical Clinical Research Code Communities Competence Computational Biology Consensus Custom DNA sequencing Data Doctor of Philosophy Enhancers Event Frequencies Gene Fusion Genes Genetic Transcription Genome Genomics Grant Immune Immunotherapy Institutes Joints Knowledge Medicine Methods Molecular Mutation New York Output Pathologist Patients Play Point Mutation Publications Publishing RNA Splicing Reporting Research Personnel Role Running Site Specific qualifier value Testing Transcriptional Regulation Untranslated RNA Variant base cancer genomics clinically relevant computer infrastructure data management design exome sequencing experience genetic variant immune checkpoint blockade improved knowledge base molecular diagnostics novel precision medicine promoter response statistics tool transcriptome sequencing tumor

项目摘要

The Weill Cornell Medicine-New York Genome Center (WCM-NYGC) for Functional and Clinical Interpretation of Tumor Profiles will perform integrative analyses of coding and non-coding variants to detect and unravel the function of specific classes of mutations and assess their clinical potential. As specified in the RFA, we have chosen to focus on two Core Competencies: (1) coding mutations and (2) non-coding mutations (germline). We will use WCM’s expertise in clinical genomics demonstrated by the first CLIA approved Whole Exome Sequencing test in New York State. We will leverage NYGC’s computational infrastructure with > 5,000 cores and 10Pb storage and data management expertise. We will focus our GDAC on specific classes of mutations: (1) coding mutations and their clinical relevance including relevance to immunotherapy; (2) driver non-coding point mutations and their role in transcriptional regulation; (3) the driving role of structural variations. In Aim 1 we will annotate the clinical and functional impact of coding mutations including immunotherapy. First we will generate a clinical grade report containing clinical interpretation of mutations, viewable through a custom user interface. This will enable detailed statistics on number and frequency of clinically relevant variants. A new module will help contribute new variants to the knowledge base and community. Second, we will apply our analytical pipeline for unraveling the immune landscape together with a novel integrative immunoscore that predicts which patients are more likely to respond to immune checkpoint blockade, a therapy showing dramatic impact in a subset of cancer patients. In Aim 2, we will annotate the driving role and impact of non-coding mutations on splicing. First, we will functionally characterize genetic variants outside of genes (promoters, enhancers) using the experimentally validated FunSeq pipeline. Second, we will analyze the transcriptional consequence of splice site alterations using a novel for integrating RNA-Seq data with predicted splice-altering variants from DNA sequencing. In Aim 3 we will annotate the driving role and transcriptional impact of structural variations. We will annotate structural variants and gene fusions using a consensus-based approach with methods benchmarked in our group as well as novel methods. The output of this Aim will be comprehensive annotation and functional analysis of a critical class of non-coding events. In summary, the proposed analyses rely on existing pipelines and tools that will be used in a standard and automated way on the WCM-NYGC computational infrastructure. The objective of these analyses is to derive novel knowledge and correlation that will impact both clinical and research cancer genomics fields. The WCM-NYGC team will participate and be responsive to the cooperative partners in this Network.

威尔康奈尔医学纽约基因组中心 (WCM-NYGC) 功能和临床肿瘤概况的解释将对编码和非编码变体进行综合分析，以检测并揭示特定类型突变的功能并评估其临床潜力。 RFA 中明确指出，我们选择关注两项核心能力：(1) 编码突变和 (2)非编码突变（种系）我们将利用WCM在临床基因组学方面的专业知识证明。我们将利用纽约州第一个 CLIA 批准的全外显子组测序测试。 NYGC 的计算基础设施拥有超过 5,000 个核心以及 10Pb 存储和数据管理我们将把 GDAC 的专业知识集中在特定类型的突变上：(1) 编码突变及其突变。临床相关性，包括与免疫治疗的相关性；（2）驱动非编码点突变和 (3)结构变化的驱动作用在目标1中我们将。首先，我们将注释编码突变（包括免疫疗法）的临床和功能影响。生成包含突变临床解释的临床等级报告，可通过自定义用户界面。这将实现临床数量和频率的详细统计。相关变体将有助于向知识库贡献新变体其次，我们将应用我们的分析流程来揭示免疫景观。结合新型综合免疫评分来预测哪些患者更有可能做出反应免疫检查点封锁是一种对部分癌症患者产生巨大影响的疗法。目标2，我们将注释非编码突变对剪接的驱动作用和影响。使用以下功能对基因之外的遗传变异（启动子、增强子）进行功能表征其次，我们将分析经过实验验证的 FunSeq 管道的转录结果。使用新颖的方法将 RNA-Seq 数据与预测的剪接改变整合起来进行剪接位点改变 DNA 测序的变体在目标 3 中我们将注释其驱动作用和转录影响。我们将使用基于共识的方法来注释结构变异和基因融合。采用我们小组的基准方法以及该目标的输出。将对一类关键的非编码事件进行全面的注释和功能分析。总之，拟议的分析依赖于将在标准中使用的现有管道和工具 WCM-NYGC 计算基础设施上的自动化方式。是获得将影响临床和研究癌症的新知识和相关性 WCM-NYGC 团队将参与并响应合作伙伴。在这个网络中。