Differences in Tumor Biology of Multiple Myeloma in Association with African Ancestry

与非洲血统相关的多发性骨髓瘤肿瘤生物学差异

• 批准号: 10656009
• 负责人: LINDA B BAUGHN
• 金额: $ 43.17万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656009
• 关键词: Accounting; Affect; African American; African American population; African ancestry; Age; Age of Onset; American; Biological Factors; Biology; Black race; Cell Line; Clinic; Clinical Trials; Cytometry; Data; Disease; Disparity; Environmental Risk Factor; European; European ancestry; Frequencies; Functional disorder; Genetic; Genetic Drift; Genetic Risk; Genetic Variation; Genomics; Goals; Health Services Accessibility; Hematopoietic Neoplasms; Human; Incidence; Individual; Malignant Neoplasms; Molecular Abnormality; Multiple Myeloma; Mutation; Newly Diagnosed; Outcome; Patients; Pharmaceutical Preparations; Plasma Cells; Prospective Studies; Public Health; Race; Regimen; Research; Retrospective Studies; Risk; Selection for Treatments; Socioeconomic Factors; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Tumor Biology; Underserved Population; Variant; cohort; drug sensitivity; genome-wide; health care availability; health difference; health disparity; improved; mortality; novel; predictive marker; prognostication; research study; response; standard of care; transcriptome sequencing; transcriptomics; treatment response; tumor; tumor microenvironment

PROJECT SUMMARY Although multiple myeloma (MM) is the most common blood cancer in Black/African American (AA) individuals, AA patients have been significantly underrepresented in MM research studies and clinical trials. MM has one of the most pronounced disparities in the incidence and mortality between AA and European American (EA) patients. As MM research has largely focused on patients of European ancestry, it remains unknown whether disparities in the incidence and outcomes of AA and EA patients are due to differences in healthcare access and/or socioeconomic, environmental, or biological factors. Large-scale studies comparing variation of the MM tumor, its tumor microenvironment (TME) and disease survival among AA patients and incorporating calculated African ancestry are critically needed. Our long-term goal is to identify important factors contributing to the health disparity in AA patients with MM. The overall objective of this proposal is to characterize the genetic variations of the MM tumor, its TME, and the impact of this variation on disease survival in a large, well-powered study of AA patients with MM. We hypothesize that AA patients have favorable MM tumor genetics but a greater immunosenescent TME, which can affect response to therapy and overall survival. The following specific aims will be evaluated: 1) Differentiate the genetic variations of MM tumors between newly diagnosed AA and EA patients; 2) Analyze the MM tumor microenvironments of newly diagnosed AA and EA patients; and 3) Compare the responses to treatment of MM tumors in newly diagnosed AA and EA patients. In specific aim 1, 1500 newly diagnosed MM patients (480 AA and 1020 EA) from two independent cohorts will be used to determine the frequency of risk-defining tumor genetic abnormalities, genome-wide genomic complexity, and mutation signatures. Differences in disease survival will be compared in relation to these risk-defining genetic abnormalities and the influence of race. In specific aim 2, 200 newly diagnosed MM patients (100 AA and 100 EA) from Mayo Clinic cohort will be used to analyze the TME signatures using RNAseq and validated using CyTOF. Differences in disease survival will be compared in relation to these TME signatures and the influence of race. In specific aim 3, 100 newly diagnosed MM patients (50 AA and 50 EA) from Mayo Clinic will be used to evaluate tumor responses to therapeutic regimens using an ex vivo drug sensitivity platform. Genetic and transcriptomic predictors of ex vivo drug response will be assessed, and top targets and novel agents will be evaluated using human myeloma cell lines. This proposal is significant because understanding MM tumor genetics and TME in AA patients will allow for improved treatment selection and prognostication in this underserved population.

项目概要 尽管多发性骨髓瘤 (MM) 是黑人/非裔美国人 (AA) 个体中最常见的血癌， AA 患者在 MM 研究和临床试验中的代表性明显不足。 MM有其中之一 AA 和欧洲美国人 (EA) 之间的发病率和死亡率差异最显着 患者。由于多发性骨髓瘤研究主要集中在欧洲血统的患者，目前尚不清楚是否 AA 和 EA 患者的发病率和结果差异是由于医疗保健获取的差异造成的 和/或社会经济、环境或生物因素。比较 MM 变化的大规模研究 AA 患者的肿瘤、肿瘤微环境 (TME) 和疾病生存率，并结合计算得出 迫切需要非洲血统。我们的长期目标是确定有助于健康的重要因素 AA 患者与 MM 的差异。该提案的总体目标是表征遗传变异 一项大型、有力的研究对 MM 肿瘤、其 TME 以及这种变异对疾病生存的影响进行了研究 AA患者合并MM。我们假设 AA 患者具有良好的 MM 肿瘤遗传学，但 免疫衰老 TME，可能影响治疗反应和总体生存率。具体目标如下 将评估： 1) 区分新诊断的 AA 和 EA 之间 MM 肿瘤的遗传变异 患者; 2）分析新诊断的AA和EA患者的MM肿瘤微环境； 3) 比较 新诊断的 AA 和 EA 患者对 MM 肿瘤治疗的反应。具体目标1，新增1500个 来自两个独立队列的确诊 MM 患者（480 名 AA 和 1020 EA）将用于确定 风险定义肿瘤遗传异常的频率、全基因组基因组复杂性和突变 签名。将根据这些风险定义遗传因素来比较疾病存活率的差异 异常和种族的影响。在具体目标 2 中，200 名新诊断的 MM 患者（100 名 AA 和 100 名 来自 Mayo Clinic 队列的 EA）将用于使用 RNAseq 分析 TME 特征，并使用 细胞飞行时间。将根据这些 TME 特征及其影响来比较疾病存活率的差异 种族。在具体目标 3 中，来自 Mayo Clinic 的 100 名新诊断的 MM 患者（50 AA 和 50 EA）将用于 使用离体药物敏感性平台评估肿瘤对治疗方案的反应。遗传和 将评估离体药物反应的转录组预测因子，并将确定顶级靶标和新药物 使用人骨髓瘤细胞系进行评估。该提议意义重大，因为了解 MM 肿瘤 AA 患者的遗传学和 TME 将改善该领域的治疗选择和预后 服务不足的人口。