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.

项目摘要 尽管多发性骨髓瘤（MM）是黑人/非洲裔美国人（AA）患者中最常见的血液癌，但 在MM研究和临床试验中，AA患者的代表性大大不足。 MM有一个 AA和欧美（EA）的发病率和死亡率上最明显的差异 患者。由于MM研究主要集中在欧洲血统的患者上，因此是否尚不清楚 AA和EA患者的发病率和结果差异是由于医疗保健访问的差异 和/或社会经济，环境或生物学因素。比较MM变化的大规模研究 肿瘤，其肿瘤微环境（TME）和AA患者的疾病存活并纳入计算 非洲血统是至关重要的。我们的长期目标是确定有助于健康的重要因素 AA患者的差异。该建议的总体目的是表征遗传变异 MM肿瘤，其TME以及这种差异对疾病存活的影响 AA患者MM。我们假设AA患者具有有利的MM肿瘤遗传学，但更大 免疫感染TME，可能会影响对治疗和总体生存的反应。以下特定目标 将评估：1）在新诊断的AA和EA之间区分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 对新诊断的AA和EA患者的MM肿瘤治疗的反应。在特定的目标1中，新近1500 将使用两个独立队列的诊断为MM患者（480 AA和1020 EA）来确定 定义风险的肿瘤遗传异常，全基因组基因组复杂性和突变的频率 签名。与这些定义风险的遗传有关的疾病生存的差异将进行比较 异常和种族的影响。在特定目标2中，有200名新诊断的MM患者（100 AA和100​​例） EA）来自Mayo诊所队列将使用RNASEQ分析TME特征并使用 细胞。将与这些TME特征相关的疾病生存差异和影响 种族。在特定的目标3中，梅奥诊所的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 将评估过体内药物反应的转录组预测指标 使用人骨髓瘤细胞系进行评估。该建议很重要，因为了解MM肿瘤 AA患者的遗传学和TME将允许改善治疗选择和预后 服务不足的人口。