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

摘要 关于分子靶标的知识，包括那些受基因异常影响的分子靶标，已经变得越来越多。 对儿童癌症精确肿瘤学至关重要。促进儿科遗传异常的探索 癌症，我们于2015年开发了山核桃(儿科癌症)知识库，以建立一个开放访问的门户网站 用于动态可视化由St.Jude和 其他机构。最近在AACR 2023上发布的PeCanV2现在可以导航遗传异常， 包括驱动突变和突变签名，在约300个分子亚型的本体论背景下 儿科癌症。通过利用PeCanV2基础设施，我们建议提高FDA的精确度- 以儿童癌症数据倡议为特征的批准的儿科分子靶点列表(PMTL) (CCDI)，以支持临床应用。这将通过1)开发生成摘要的API来实现 通过汇总儿童癌症队列统计癌症亚型水平上的遗传异常 多项倡议和山核桃的协调(目标1)；2)扩大儿童癌症的知识库 整合三个CCDI数据集(即CCDI MSKCC临床WGS、CCDI分子)的遗传异常 特征和CCDI转移性神经母细胞瘤)，已经有大约9000个儿科癌症样本 由圣犹大山核桃门户网站协调和管理(目标2)；以及3)进行突变特征分析 使用最先进的全基因组测序技术对CCDI样本进行癌症亚型水平的分析 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， 在领导世界上最大的儿科癌症基因组研究和数据共享方面有既定的记录 努力。拟议工作的完成将对稀有或罕见的分子驱动因素产生新的见解 超罕见的儿科癌症亚型，而PMTL在分子亚型水平的交集将 大大增强了其临床应用价值。因此，我们的建议解决了RFA提出的关键问题 并与《中纪委补编》高度相关，涉及《数据聚合、链接、集成、分析 和可视化“、”超罕见肿瘤分析“和”FDA相关分子靶标清单的验证“。

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”.