Enhancing Precision of Pediatric Cancer Molecular Targets by Aggregating CCDI Genomic Data to Pediatric Cancer Knowledgebase

将CCDI基因组数据汇总到小儿癌症知识库，提高小儿癌症分子靶点的精准度

• 批准号: 10877602
• 负责人: CHARLES ROBERTS
• 金额: $ 49.92万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10877602
• 关键词: Address; Affect; American Association of Cancer Research; Childhood; Clinical; Data; Data Aggregation; Data Set; FDA approved; Individual; Infrastructure; Institution; Knowledge; Literature; Malignant Childhood Neoplasm; Memorial Sloan-Kettering Cancer Center; Molecular; Molecular Abnormality; Molecular Target; Mutation; Neuroblastoma; Ontology; Publishing; Research Personnel; Saint Jude Children' s Research Hospital; Sampling; Software Engineering; Validation; Variant; Visualization; Work; cancer genomics; cancer subtypes; clinical application; cohort; data sharing; driver mutation; genome sequencing; genomic data; insight; knowledgebase; molecular subtypes; precision oncology; rare cancer; statistics; whole genome

ABSTRACT Knowledge about molecular targets, including those affected by genetic abnormality, has become increasingly critical for childhood cancer precision oncology. To facilitate exploration of genetic abnormality in pediatric cancer, we developed PeCan (Pediatric Cancer) Knowledgebase in 2015 to establish an open access portal for dynamic visualization of curated somatic variants from published literature contributed by St. Jude and other institutions. PeCanV2, recently released at AACR 2023, now enables navigation of genetic abnormality, including driver mutations and mutational signatures, in the context of ontology of ~300 molecular subtypes of pediatric cancer. By leveraging the PeCanV2 infrastructure, we propose to enhance the precision of FDA- approved Pediatric Molecular Target List (PMTL), characterized by the Childhood Cancer Data Initiative (CCDI), to support clinical applications. This will be achieved by 1) developing an API to generate summary statistics of genetic abnormality at cancer subtype level by aggregating pediatric cancer cohorts profiled by multiple initiatives and harmonized by PeCan (Aim 1); 2) expanding the knowledgebase of pediatric cancer genetic abnormality by integrating three CCDI data sets (i.e. CCDI MSKCC Clinical WGS, CCDI Molecular Characterization and CCDI Metastatic Neuroblastoma), with ~9,000 pediatric cancer samples already harmonized and curated by the St. Jude PeCan portal (Aim 2); and 3) performing mutational signature analysis at cancer subtype level for CCDI samples profiled by whole-genome sequencing using the state-of-art pipelines that we developed (Aim 3). Our team is comprised of researchers and software engineers who have an established track record of leading the world’s largest pediatric cancer genomic studies and data sharing effort. The completion of the proposed work will generate new insights into the molecular drivers of rare or ultra-rare subtypes of pediatric cancer, while the intersection of the PMTL at molecular subtype level will greatly enhance its clinical application. Our proposal thus addresses the key questions put forth by the RFA and is highly relevant to the CCDI Supplement with regards to “data aggregation, linkage, integration, analysis and visualization”, “ultra-rare tumor analysis” and “validation of the FDA Relevant Molecular Target List”.

摘要 关于分子靶点的知识，包括那些受遗传异常影响的靶点，已经变得越来越多， 对于儿童癌症精准肿瘤学至关重要。为了促进儿童遗传异常的探索， 癌症，我们在2015年开发了PeCan（儿科癌症）知识库，以建立一个开放的访问门户网站 用于动态可视化来自St. Jude贡献的已发表文献的策划体细胞变体， 其他机构。最近在AACR 2023上发布的PeCanV 2现在可以导航遗传异常， 包括驱动突变和突变签名，在约300种分子亚型的本体论背景下， 儿科癌症通过利用PeCanV 2基础设施，我们建议提高FDA的精度- 经批准的儿科分子靶点列表（PMTL），由儿童癌症数据倡议组织表征 （CCDI），以支持临床应用。这将通过1）开发一个API来生成摘要 通过汇总儿科癌症队列分析的癌症亚型水平的遗传异常统计 PeCan（目标1）的多项举措和协调; 2）扩大儿科癌症的知识基础 通过整合三个CCDI数据集（即CCDI MSKCC Clinical WGS，CCDI Molecular 表征和CCDI转移性神经母细胞瘤），已经有约9，000例儿科癌症样本 由St. Jude PeCan门户网站协调和策划（Aim 2）;和3）进行突变特征分析 在癌症亚型水平上，使用最先进的全基因组测序对CCDI样本进行分析 我们开发的管道（目标3）。我们的团队由研究人员和软件工程师组成， 领先世界上最大的儿科癌症基因组研究和数据共享的既定记录 努力完成拟议的工作将产生新的见解的分子驱动程序的罕见或 超罕见的儿科癌症亚型，而PMTL在分子亚型水平的交叉将 大大提高了其临床应用。因此，我们的建议解决了RFA提出的关键问题 并与CCDI补充文件中关于“数据聚合、链接、集成、分析”的内容高度相关 和可视化”、“超罕见肿瘤分析”和“FDA相关分子靶点列表的验证”。