Adapting Functional Precision Oncology for pediatric brain cancer

采用功能精准肿瘤学治疗小儿脑癌

• 批准号: 10227337
• 负责人: Gabor T Marth
• 金额: $ 15.24万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227337
• 关键词: Adult; Algorithmic Software; Algorithms; Area; Behavior; Brain Neoplasms; Cancer Patient; Cells; Child; Childhood; Childhood Brain Neoplasm; Childhood Malignant Brain Tumor; Copy Number Polymorphism; DNA sequencing; Data; Data Set; Development; Disseminated Malignant Neoplasm; Drug Screening; Evolution; Foundations; Funding; Gene Expression; Genomics; Informatics; Malignant Childhood Neoplasm; Malignant Neoplasms; Methods; Modification; Mutation; Patients; Pediatric Neoplasm; Point Mutation; Population Heterogeneity; Process; Selection for Treatments; Testing; Universities; Utah; Visualization software; base; cohort; computerized tools; experience; indexing; neoplastic cell; parent grant; parent project; precision oncology; reconstruction; single-cell RNA sequencing; tool; tool development; transcriptomics; treatment choice; tumor; tumor heterogeneity

ABSTRACT Cancers are typically composed of heterogeneous populations of tumors cells characterized by mutations that distinguish each cell subpopulation from one another. The parent grant leverages DNA sequencing and a suite of important new analytical algorithms and visualization tools to identify mutations in cancer patients and track the evolution of a patient’s tumor over the course of treatment. The tools we have developed, or are in the process of developing, form the foundation of a functional precision oncology approach we are implementing at the University of Utah with a combination of set-aside funding from the parent project, and institutional funding. The current Supplemental Request will adapt the tools funded by the parent project for effective use in pediatric cancers. The main objective of this Supplemental Proposal is to adapt our functional precision oncology approach to inform treatment selection in children with brain tumors, a patient cohort that experiences extremely dire prognoses in which rational treatment choice is difficult without precision guidance. There are compelling reasons to believe, however, that such adaptation will require algorithmic modifications. This is because key aspects of our approach rely on genomic mutations in the tumor, but previous studies show that pediatric tumors have a substantially lower mutation load than adult cancers. Therefore it is necessary to expand our functional approach in pediatric cases, and adapt them to lower mutation loads in pediatric tumors. To accomplish such adaptation, we will, first, perform functional drug screening and genomic/transcriptomic characterization in two pediatric brain cancer index patients, so we have appropriate test cases drivin our tool development and testing. We will then, second, analyze the pediatric brain tumor index patient datasets, and adapt our functional precision informatics methods for use in pediatric brain tumors with expected lower genomic mutation loads. We foresee two specific areas of development: because of the substantially lower number of mutations in the pediatric cases, we will integrate the ability to simultaneously analyze somatic copy number variation (CNV) mutations, together with somatic point mutations to (1) reconstruct the genomic subclones that make up the tumor; and (2) to carry out cell assignment to the genomically defined sublones from single-cell RNA sequencing data used to study tumor subclone-specific gene expression behavior. We have already shown that CNVs can be used both for tumor subclone reconstruction and cell assignment, and anticipate that by integrating CNV and point mutation- based analyses in a single tool will allow functional precision analysis of pediatric cancer patients at, or close to, the level achievable for adult patients. 1

抽象的 癌症通常由异质肿瘤细胞群组成，其特征是突变 父资助利用 DNA 测序和一套套件来区分每个细胞亚群。 重要的新分析算法和可视化工具，用于识别癌症患者的突变并进行跟踪 我们已经开发或正在开发的工具，可以帮助我们了解患者肿瘤在治疗过程中的演变。 开发过程，形成我们正在实施的功能性精准肿瘤学方法的基础 犹他大学，结合了母项目的预留资金和机构资金。 当前的补充请求将调整父项目资助的工具，以便在儿科中有效使用 该补充提案的主要目标是调整我们的功能性精准肿瘤学。 为患有脑肿瘤的儿童提供治疗选择的方法，这是一个经历了极端的患者群体 如果没有精确的指导，很难做出合理的治疗选择，这会导致可怕的预后。 然而，有理由相信这种适应将需要算法修改，这是因为关键。 我们的方法的各个方面依赖于肿瘤中的基因组突变，但之前的研究表明儿童肿瘤 与成人癌症相比，突变负荷要低得多，因此有必要扩展我们的功能。 儿科病例的方法，并使其适应降低儿科肿瘤的突变负荷以实现这一目标。 适应，我们首先将在两个方面进行功能药物筛选和基因组/转录组表征 儿科脑癌指数患者，因此我们有适当的测试用例来推动我们的工具开发和测试。 其次，我们将分析儿科脑肿瘤指数患者数据集，并调整我们的功能精度 我们预计，信息学方法可用于治疗具有较低基因组突变负荷的儿科脑肿瘤。 两个具体的发展领域：由于儿科病例中的突变数量大幅减少， 我们将整合同时分析体细胞拷贝数变异（CNV）突变的能力 通过体细胞点突变（1）重建构成肿瘤的基因组亚克隆；（2）携带 从用于研究的单细胞 RNA 测序数据中将细胞分配给基因组定义的亚克隆 我们已经证明 CNV 可以用于肿瘤亚克隆特异性基因表达行为。 肿瘤亚克隆重建和细胞分配，并通过整合CNV和点突变来预测- 基于单一工具的分析将允许对儿科癌症患者进行功能精确分析，达到或接近 成年患者可达到的水平。 1

项目成果

Rapid clinical diagnostic variant investigation of genomic patient sequencing data with iobio web tools.

使用 iobio 网络工具对基因组患者测序数据进行快速临床诊断变异研究。

• DOI: 10.1017/cts.2017.311
• 发表时间: 2017
• 期刊: Journal of clinical and translational science
• 影响因子: 2.6
• 作者: Ward,Alistair;Karren,MaryA;DiSera,Tonya;Miller,Chase;Velinder,Matt;Qiao,Yi;Filloux,FrancisM;Ostrander,Betsy;Butterfield,Russell;Bonkowsky,JoshuaL;Dere,Willard;Marth,GaborT
• 通讯作者: Marth,GaborT