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 虽然多发性骨髓瘤（MM）是黑人/非裔美国人（AA）个体中最常见的血癌， 在MM研究和临床试验中，AA患者的代表性明显不足。MM有一个 AA和欧洲裔美国人（EA）之间的发病率和死亡率差异最明显 患者由于MM研究主要集中在欧洲血统的患者， AA和EA患者的发病率和结局的差异是由于医疗服务的差异 和/或社会经济、环境或生物因素。比较MM变异的大规模研究 肿瘤，其肿瘤微环境（TME）和AA患者的疾病生存率，并结合计算 非洲血统是非常必要的。我们的长期目标是确定影响健康的重要因素， 该建议的总体目标是描述AA患者与MM的遗传变异特征。 MM肿瘤、其TME以及这种变异对疾病生存期的影响， 我们假设AA患者具有有利的MM肿瘤遗传学，但更大的MM肿瘤遗传学。 免疫衰老TME，其可影响对治疗的反应和总体存活。以下具体目标 将评估：1）区分新诊断的AA和EA之间MM肿瘤的遗传变异 2）分析新诊断的AA和EA患者的MM肿瘤微环境;和3）比较 新诊断AA和EA患者对MM肿瘤治疗的反应。在具体目标1，1500新 来自两个独立队列的确诊MM患者（480例AA和1020例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.疾病生存率的差异将与这些风险定义基因进行比较。 异常和种族的影响。在具体目标2中，200例新诊断的MM患者（100例AA和100例 将使用来自马约诊所队列的TME标签（EA），使用RNAseq分析TME标签，并使用 CyTOF。将比较疾病生存率的差异与这些TME特征的关系， 种族。在具体目标3中，来自马约诊所的100例新诊断的MM患者（50例AA和50例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学预测因子，并将评估最佳靶点和新型药物。 使用人骨髓瘤细胞系评价。这一建议是有意义的，因为了解MM肿瘤 遗传学和TME在AA患者中的应用将允许改善治疗选择和治疗， 服务不足的人口。