Defining the landscape of structural alterations in African American Multiple Myeloma

定义非裔美国人多发性骨髓瘤的结构改变

• 批准号: 10651845
• 负责人: Lawrence H. Boise
• 金额: $ 21.51万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10651845
• 关键词: 13q; 17p; 1q21; Address; Admixture; African American; African American population; Age; American; Autologous Transplantation; Basic Science; Bone Marrow; Bortezomib; CCND1 gene; Caucasians; Cessation of life; Chromosomes; Clinical; Consent; DNA Sequence Alteration; Data; Data Set; Development; Dexamethasone; Diagnosis; Disease; Disease Outcome; Disease Progression; Enhancers; European; Event; FGFR3 gene; Frequencies; Gene Expression Profile; Genetic; Genome; Genomics; Goals; Heavy-Chain Immunoglobulins; Hematologic Neoplasms; Hybrids; Immunoglobulins; Incidence; Institution; KRAS2 gene; Light; Maintenance Therapy; Malignant Neoplasms; Measures; Monoclonal gammopathy of uncertain significance; Multiple Myeloma; Mutation; Newly Diagnosed; Oncogenes; Onset of illness; Outcome; Patient Self-Report; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Plasma Cells; Population; Prognosis; Prognostic Marker; Race; Reporting; Resistance; Revlimid; Risk Factors; Sampling; System; TP53 gene; Testing; Therapeutic; Trisomy; Universities; Variant; Velcade; Vertebral column; design; diagnosis standard; disorder risk; early detection biomarkers; early onset; experience; genetic testing; genome sequencing; health disparity; high risk; improved; kappa-Chain Immunoglobulins; lenalidomide; overexpression; risk prediction; standard of care; therapy outcome; transplantation therapy; treatment response; whole genome

Summary Multiple Myeloma is a malignancy of long-lived plasma cells of the bone marrow and is the second most common hematologic malignancy, with over 34,000 new cases and nearly 13,000 deaths expected in the US in 2021. However, amongst African Americans, myeloma is the most common hematologic malignancy with the incidents rate between 2-3 times higher than that observed in Caucasians. Consistent with this finding, the precursor to myeloma, Monoclonal Gammopathy of Undetermined Significance (MGUS) is also observed at a higher frequency in African Americans. Thus, the increased frequency of myeloma is likely to due to underlying factors that result in both the development of MGUS as well as its progression to myeloma. Translocations that juxtapose oncogenes to the potent enhancers of the immunoglobulin heavy chain (IgH) or trisomies of odd- numbered chromosomes (hyperdiploidy) are the initiating events in nearly all myelomas. However, these are rarely sufficient to cause myeloma, which almost always have additional copy number alterations (e.g., del17p, amp1q21) and/or mutations (e.g. KRAS, TP53) observed at diagnosis and these influence outcome. Interestingly African Americans tend to have genomic alterations that would predict a superior outcome, however we have found that in patients treated identically with the current standard of care at our institution, there is no difference in the patient outcomes. Additionally, in the MMRF CoMMpass study, African Americans do worse than Caucasians despite no difference in the treatment and being diagnosed at a significantly earlier age, which is typically considered a good prognostic marker. Together these data suggest that our current approaches are either not accurately predicting risk or our therapeutic approaches are not optimized for the African American population. Our recent finding suggest that these events could be related. Utilizing whole genome sequencing that is part of the MMRF CoMMpass study, we performed an analysis of the structural landscape of newly diagnosed multiple myeloma. We found that patients that have translocations in the immunoglobulin lambda light chain locus (IgL) have a significantly worse outcome than other patients in the study. IgL translocations were found in 10% of the population and 70% were associated with hyperdiploid myeloma, a good prognostic marker routinely tested for clinically whereas IgL events are not. Thus, these patients were misdiagnosed with lower risk disease. We also demonstrated that the likely cause of misdiagnosis was resistance to one of the backbone myeloma drugs, lenalidomide. African American patients with IgL translocations experienced strikingly worse outcomes than their European American counterparts. Based on these findings we hypothesize that there are additional structural events that are not routinely tested for which can influence outcomes and that these may differ in African American myeloma. These events may also contribute to the early onset of disease. We propose two Specific Aims to test this hypothesis as well as the development of a test to detect these changes.

总结 多发性骨髓瘤是骨髓中长寿命浆细胞的恶性肿瘤， 血液恶性肿瘤，预计2021年美国将有超过34，000例新发病例和近13，000例死亡。 然而，在非洲裔美国人中，骨髓瘤是最常见的血液恶性肿瘤， 比在高加索人中观察到的高2-3倍。与这一发现相一致的是， 骨髓瘤，意义不明的单克隆丙种球蛋白病（MGUS）也在较高的 非洲裔美国人的频率。因此，骨髓瘤发生率的增加可能是由于潜在因素 导致MGUS的发展以及其向骨髓瘤的进展。的易位 将癌基因与免疫球蛋白重链（IgH）的有效增强子或奇- 编号的染色体（超二倍体）是几乎所有骨髓瘤的起始事件。不过这些都是 很少足以引起骨髓瘤，其几乎总是具有额外的拷贝数改变（例如，del17p， amp 1 q21）和/或突变（如KRAS，TP 53），这些影响结果。 然而，有趣的是，非洲裔美国人倾向于有基因组改变，这将预测一个上级的结果， 我们发现，在我们机构采用当前标准治疗的患者中， 患者结果的差异。此外，在MMRF CoMMPass研究中，非洲裔美国人的表现更差。 尽管在治疗上没有差异，而且在明显更早的年龄被诊断出来， 通常被认为是良好的预后标志物。这些数据表明，我们目前的方法是 要么不能准确预测风险，要么我们的治疗方法不适合非洲裔美国人， 人口我们最近的发现表明这些事件可能是相关的。利用全基因组测序 这是MMRF CoMMPass研究的一部分，我们对新的 诊断为多发性骨髓瘤我们发现免疫球蛋白λ易位的患者 轻链基因座（IgL）的患者比研究中的其他患者具有显著更差的结果。IgL易位 在10%的人群中发现，70%与超二倍体骨髓瘤相关， 标记物进行常规临床检测，而IgL事件则不进行。因此，这些患者被误诊为 低风险疾病。我们还证明了误诊的可能原因是对其中一种 骨髓瘤骨干药物来那度胺患有IgL易位的非洲裔美国人患者经历了惊人的 结果比欧洲的美国同行更糟糕。基于这些发现，我们假设， 是额外的结构性事件，这些事件没有进行常规测试，可能会影响结果， 可能与非裔美国人骨髓瘤不同。这些事件也可能导致疾病的早期发作。我们 提出了两个具体目标来检验这一假设，以及一个测试来检测这些变化的发展。