Deep Sequencing of Relapse and Refractory Hodgkin Lymphoma Genomes: A Study of Tumor Biology and Evolution

复发和难治性霍奇金淋巴瘤基因组的深度测序：肿瘤生物学和进化的研究

• 批准号: 10351582
• 负责人: Felicia Gomez
• 金额: $ 19.45万
• 依托单位: WASHINGTON UNIVERSITY
• 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 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10351582
• 关键词: Address; Affect; Aftercare; Architecture; Automobile Driving; B-Lymphocytes; Bioinformatics; Biological Markers; Biology; Cancer Biology; Cells; Clinical; Collection; DNA; Data; Development; Diagnosis; Disease; Disease Outcome; Evolution; Genes; Genome; Genomics; Goals; Heterogeneity; Hodgkin Disease; Location; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Methodology; Methods; Molecular; Monitor; Morphology; Mutate; Mutation; Mutation Detection; Needs Assessment; Newly Diagnosed; Normal tissue morphology; Outcome; Pathway interactions; Patients; Plasma; Population; Prediction of Response to Therapy; Predictive Factor; Primary Neoplasm; Prognosis; Reagent; Recurrence; Reed-Sternberg Cells; Refractory; Relapse; Research; Resistance; Risk Assessment; Salvage Therapy; Sampling; Signal Transduction; Somatic Mutation; Source; Statistical Methods; Techniques; Technology; Testing; Therapeutic; Training; Tumor Biology; Universities; Variant; Washington; Western World; anticancer research; biomarker identification; cancer cell; cancer genomics; cancer type; cell free DNA; cell type; clinically relevant; cohort; deep sequencing; design; exome; exome sequencing; experimental study; genome-wide; improved; innovation; large datasets; lymph nodes; medical schools; mutational status; new therapeutic target; next generation sequencing; predictive marker; programs; standard of care; targeted treatment; therapy resistant; tool; treatment response; tumor; tumor microenvironment

Hodgkin lymphoma (HL) accounts for ten percent of all lymphomas in the western world and remains a substantial clinical problem. Relapsed and refractory (R/R) HL presents a particularly critical unmet clinical need because approximately 25% of HL patients will be refractory to the standard of care or will relapse while receiving treatment, and the overall survival of R/R HL patients is ~50%. New targeted treatment options and improved risk assessment are needed to improve the therapeutic options for these patients. HL is defined by a rare malignant B cell (Hodgkin-Reed-Sternberg , HRS cells) that occupies a small fraction of the tumor microenvironment. Despite many advances in next generation sequencing technologies, the identification of somatic variants in cancers characterized by rare cell populations remains technically and analytically challenging. These obstacles have resulted in a limited number of studies that have used high throughput genome-wide technologies to characterize the genomic landscape of newly diagnosed HL, and far fewer have attempted to use these technologies to address the genomic landscape of R/R HL. Here, we address this shortfall by asking three questions: 1) Can ultra-deep genome-wide sequencing, paired with analysis and filtering strategies optimized for low VAF variants identify somatic variants driving treatment resistance in R/R HL? 2) Can we use somatic mutation status in a large cohort of newly diagnosed and R/R HL to identify genes that are predictive of response to therapy? 3) Can somatic mutations identified in genomic and/or cell free DNA describe clonal heterogeneity among HRS cells and can cell free DNA serve as biomarker of HL at diagnosis or relapse? This research will be broadly impactful because: 1) it will describe the genomic landscape of R/R HL and will identify biomarkers that are predictive of poor response to treatment; 2) it will begin to address the relationship between clonal architecture in HL, disease outcome, and prognosis; 3) it will further define cfDNA as a suitable target for HL disease monitoring By completing this proposal Dr. Felicia Gomez will gain advanced training in genomics, bioinformatics, lymphoma biology, and cancer biology in general. This proposal takes advantage of the cutting edge genomics and cancer research at Washington University School of Medicine (WUSM). WUSM is an ideal location to complete the experiments and training described in this proposal. Dr. Gomez is a well-trained scholar who is poised to develop a program of research that will be innovative and responsive to the need for diversity in the biomedical workforce. When Dr. Gomez transitions to independence she will continue to focus on cancer genomics and will broaden her research to address the interactions between somatic and germline variation and how this interaction affects the development and progression of lymphoma and other malignancies.

霍奇金淋巴瘤（HL）占西方世界所有淋巴瘤的百分之十 实质性临床问题。复发和耐火（R/R）HL提出了特别关键的未经临床 需要，因为大约25％的HL患者将对护理标准感到难治或会复发 接受治疗，R/R HL患者的总体存活率约为50％。新的目标治疗选择和 需要改善风险评估以改善这些患者的治疗选择。 HL由 罕见的恶性B细胞（Hodgkin-Reed-Sternberg，HRS细胞）占据了一小部分肿瘤 微环境。尽管下一代测序技术取得了许多进步，但识别 以稀有细胞群体为特征的癌症中的体细胞变异在技术上和分析上仍然存在 具有挑战性的。这些障碍导致了有限的研究，这些研究使用了高通量 全基因组的技术来表征新诊断的HL的基因组景观，而更少 试图使用这些技术来解决R/R HL的基因组景观。在这里，我们解决这个问题 提出三个问题的短缺：1）可以超深基因组测序，与分析和 针对低VAF变体优化的过滤策略识别驱动治疗耐药性的体细胞变体 HL？ 2）我们可以在大量的新诊断和R/R HL中使用体细胞突变状态以识别基因 可以预测对治疗的反应？ 3）可以在基因组和/或无细胞中鉴定的体细胞突变 DNA描述了HRS细胞之间的克隆异质性，可以无细胞DNA充当HL的生物标志物 诊断或复发？这项研究将具有广泛的影响，因为：1）它将描述基因组 R/R HL的景观，将确定可预测治疗反应不佳的生物标志物； 2）会 开始解决HL中克隆建筑，疾病结局和预后之间的关系； 3）会 进一步将CFDNA定义为HL疾病监测的合适目标 通过完成这项建议，Felicia Gomez博士将获得基因组学，生物信息学的高级培训， 淋巴瘤生物学和癌症生物学一般。该建议利用了最前沿的基因组学 华盛顿大学医学院（WUSM）的癌症研究。 WUSM是一个理想的位置 完成本提案中描述的实验和培训。戈麦斯博士是一位训练有素的学者，他是 准备制定一项研究计划，该计划将是创新的，并且响应于对多样性的需求 生物医学劳动力。当戈麦斯博士过渡到独立时，她将继续专注于癌症 基因组学并将扩大她的研究以解决躯体和种系变化之间的相互作用 以及这种相互作用如何影响淋巴瘤和其他恶性肿瘤的发展和进展。