Precision Approaches to Treat Mantle Cell Lymphoma: Integrating Multi-omics Based Models

治疗套细胞淋巴瘤的精准方法：整合基于多组学的模型

• 批准号: 10530111
• 负责人: Holly Ann Hill
• 金额: $ 3.47万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10530111
• 关键词: Affect; Age; Alcohol consumption; Area; Biological; Biological Assay; CCND1 gene; CDKN2A gene; Cancer Patient; Characteristics; Clinical; Clinical Research; Computer software; Computing Methodologies; Correlative Study; DNA; DNA sequencing; Data; Data Set; Databases; Diagnostic; Disease; Disease Progression; Disease stratification; Drug Targeting; Environmental Exposure; Epigenetic Process; Frequencies; Functional disorder; Gene Expression; Gene Expression Profile; Genes; Genetic Heterogeneity; Genetic Transcription; Genome; Genomic Instability; Genomics; Glean; Hematopoiesis; Holly; Individual; Investigation; Knowledge; Laboratories; Link; Malignant Neoplasms; Mantle Cell Lymphoma; Measurement; Meta-Analysis; Methods; Modeling; Molecular; Molecular Abnormality; Morphology; Mutate; Mutation; Mutation Analysis; NOTCH1 gene; Non-Hodgkin' s Lymphoma; Other Genetics; Outcome; Output; Pathway Analysis; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phase; Precision Medicine Initiative; Precision medicine trial; Prevalence; Principal Component Analysis; Prognosis; Race; Radiation exposure; Relapse; Reporting; Research; Research Project Grants; Resistance; Sample Size; Sampling; Single Nucleotide Polymorphism; Smoking; Statistical Models; TP53 gene; Techniques; The Cancer Genome Atlas; Translating; University of Texas M D Anderson Cancer Center; Variant; analytical method; base; cancer type; circular RNA; clinical investigation; clinically relevant; complex biological systems; computerized tools; differential expression; epigenomics; exome sequencing; feature selection; genetic analysis; genome sequencing; imprint; individual patient; innovation; insight; lifestyle factors; liquid biopsy; multiple omics; mutational status; next generation sequencing; novel; personalized approach; personalized medicine; personalized therapeutic; pre-doctoral; prognostic; prognostic of survival; response; sex; survival outcome; targeted treatment; therapy resistant; transcriptome sequencing; transcriptomics; treatment response; tumor DNA; tumor microenvironment; whole genome

Project Summary Mantle cell lymphoma (MCL) is a rare, incurable form of non Hodgkin lymphoma which is disposed to therapeutic resistance and relapse. Though rare, MCL is both clinically and genetically heterogenous and represented by multiple subtypes. It is presently unknown how various genomic features impact the clinical course of MCL and how these biological aspects contribute to treatment resistance and disease progression. It is difficult to study the molecular features of MCL due to its rarity and lack of representation in accessible databases like the cancer genome atlas (TCGA). Additionally, it is currently challenging to integrate -omics features in precision medicine initiatives due to the vast size of data from sequencing and unclear biological and clinical relevance of singular mutational and transcriptional features. It is also difficult to study these features in combination with demographic and other relevant individual features. In the F99 phase of the proposed dissertation research project, Holly Hill will employ novel analytical and computational methods to integrate multi-omics datasets in a pooled analysis of MCL patients. These analyses will include genomics, transcriptomics, epigenomics and features of the clinical exposome. Feature selection and variable reduction techniques will be used as appropriate. These sub-analyses will identify biological correlates and generate composite variables which will be used in univariate and multivariate models to examine clinical outcomes in MCL including drug response and survival. The KOO phase of the proposed activities will include further investigations into MCL and other cancers utilizing knowledge gained from the dissertation project (F99). Insights acquired during the F99 phase will also be used to develop targeted assays that simplify the mutational or transcriptional profiles of MCL into clinically useful and valid applications. Serial -omics measurements will be integrated into correlative genomics studies and precision medicine trials which will include sequencing from liquid biopsies or circulating tumor DNA (ctDNA). The proposed efforts will produce insights into condensing and translating data from -omics studies into the clinical space. It is hoped that the findings of this study will inform methods suitable for precision medicine trials and help achieve our long-term objective to personalize therapeutics for individual cancer patients.

项目概要 套细胞淋巴瘤 (MCL) 是一种罕见且无法治愈的非霍奇金淋巴瘤 治疗抵抗和复发。尽管很少见，但 MCL 在临床和遗传上均具有异质性 由多个亚型表示。目前尚不清楚各种基因组特征如何影响临床 MCL 的病程以及这些生物学方面如何影响治疗抵抗和疾病进展。它 由于 MCL 的稀有性和缺乏代表性，因此很难研究 MCL 的分子特征。 癌症基因组图谱 (TCGA) 等数据库。此外，目前整合组学具有挑战性 由于测序数据量大且生物学不明确，精准医疗计划的特点 以及单一突变和转录特征的临床相关性。研究这些也很困难 特征与人口统计和其他相关个人特征相结合。 在拟议论文研究项目的 F99 阶段，Holly Hill 将采用新颖的分析和方法 将多组学数据集整合到 MCL 患者汇总分析中的计算方法。这些分析 将包括基因组学、转录组学、表观基因组学和临床暴露组的特征。特征选择 并且将酌情使用变量减少技术。这些子分析将确定生物 关联并生成复合变量，这些变量将在单变量和多变量模型中使用 检查 MCL 的临床结果，包括药物反应和生存。 拟议活动的 KOO 阶段将包括进一步研究 MCL 和其他癌症，利用 从论文项目（F99）中获得的知识。 F99 阶段获得的见解也将被使用 开发靶向测定法，将 MCL 的突变或转录谱简化为临床有用的 以及有效的申请。连续组学测量将被整合到相关基因组学研究中 精准医学试验将包括液体活检或循环肿瘤 DNA (ctDNA) 的测序。 拟议的工作将产生对组学研究数据的浓缩和转化的见解。 临床空间。希望这项研究的结果将为适合精准医学试验的方法提供信息 并帮助实现我们为个体癌症患者提供个性化治疗的长期目标。