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

项目总结 尽管多发性骨髓瘤(MM)是黑人/非裔美国人(AA)最常见的血癌， 再生障碍性贫血患者在MM研究和临床试验中的代表性明显不足。MM有一项 再生障碍性贫血和欧洲美洲人(EA)之间发病率和死亡率的最显著差异 病人。由于多发性骨髓瘤的研究主要集中在欧洲血统的患者身上，目前尚不清楚 再生障碍性贫血和EA患者的发病率和预后的差异是由于获得医疗保健的不同 和/或社会经济、环境或生物因素。比较MM变异的大规模研究 再生障碍性贫血患者的肿瘤及其肿瘤微环境(TME)和疾病存活率 非洲血统是迫切需要的。我们的长期目标是确定对健康有贡献的重要因素 再生障碍性贫血合并多发性骨髓瘤患者的差异。这项建议的总体目标是表征遗传变异。 MM肿瘤及其TME的关系，以及这种变异对疾病存活率的影响 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 免疫衰退性TME，可影响治疗反应和总存活率。以下是具体目标 将评估：1)区分新诊断的AA和EA的MM肿瘤的基因变异 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肿瘤的治疗反应。在具体目标1,1500个新 来自两个独立队列的确诊多发性骨髓瘤患者(480名AA和1020名EA)将被用于确定 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。疾病存活率的差异将与这些定义风险的基因进行比较 异常和种族的影响。在特定目标中，2200名新诊断的MM患者(100名AA和100名 来自Mayo诊所队列的Ea)将用于使用RNAseq分析TME签名，并使用 CyTOF。疾病存活率的差异将与这些TME特征及其影响进行比较 种族的问题。在特定的目标3,100名来自梅奥诊所的新诊断的MM患者(50名AA和50名EA)将用于 使用体外药物敏感性平台评估肿瘤对治疗方案的反应。遗传和 体外药物反应的转录预测因子将被评估，顶级靶点和新药将被 使用人骨髓瘤细胞系进行评估。这一建议具有重要意义，因为对MM肿瘤的理解 再生障碍性贫血患者的遗传学和TME将允许改善治疗选择和预后 服务不足的人口。

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.