Molecular prediction of myeloma in African Americans

摘要 多发性骨髓瘤(MM)几乎总是在早期先兆条件之前：单克隆性伽玛病 意义不明(MGUS)和阴燃骨髓瘤(SMM)。大约3%的人口&50年 患有MGUS，使其成为一种非常常见的前驱症状。有家庭的人患此病的风险要高2-3倍。 MM或黑人/非裔美国人(AA)的历史。在这里，我们认为，不是用种族和 仅限家族史，我们将风险定义为特定的基因组签名，其中一些与种族有关。通过 筛查MGUS的高危人群，可以为患者制定早期预防和拦截策略 谁将从早期治疗干预中受益。我们的初步数据确定了MGUS的流行率 约13%的高危人群；数据来自两个来源：我们的前瞻性队列研究(The Promise 研究)正在对30,000名有患多发性骨髓瘤风险的参与者进行筛查，并建立大型回溯性组织库 研究，MASH-General Brigham(MGB)生物库，有123,000名受试者。然而，缺少的是 多发性骨髓瘤的生物致癌风险机制的识别及其转化为癌症 拦截和早期治疗干预。这种方法将允许场从一个纯粹的 生物学风险的人口统计学定义。我们相信，来自PLCO研究的样本，以及我们的 目前的研究队列，可以帮助确定导致癌症发生过程的机制基础 MGUS/MM。我们的首要假设是，在 基因组水平可以更准确地识别特定的风险人群，而不是人口属性和 确定早期拦截的重点策略。在具体目标1中，我们定义了单克隆性的流行 PLCO研究中高危参与者的伽马病以及MGB/Promise队列和特征 它们对长期健康结果的影响。在特定的目标2中，我们确定了容易发生 开发MGUS/MM我们的目标是描述与种族和家庭相关的风险的遗传基础 病史。我们希望这种方法将允许我们不再使用自我报告的比赛状态 风险分层。在特定的目标3中，我们评估了免疫老化在MGUS/MM发生中的作用。 传统上被认为是老年人的一种疾病，但这种风险可能可以更好地解释为 起源而不是按时间顺序排列的年龄。 这种方法将使我们能够从纯粹的人口定义过渡到 对生物性疾病的风险。

SUMMARY Multiple Myeloma (MM) is almost always preceded by early precursor conditions: monoclonal gammopathy of undetermined significance (MGUS) and smoldering myeloma (SMM). About 3% of the population >50 years have MGUS, making it a very common precursor condition. The risk is 2-3 times higher in people with a family history of MM or who are Black/African American (AA). Here, we believe that instead of defining risk by race and familial history only, we will define risk as specific genomic signatures, some of which are related to race. By screening at-risk populations for MGUS, one can develop early prevention and interception strategies for patients who would benefit from early therapeutic interventions. Our preliminary data identified an MGUS prevalence of ~13% in high-risk populations; the data came from two sources: our prospective cohort study (the PROMISE study) that is screening 30,000 participants at-risk of developing MM and a large retrospective tissue banking study, the Mass-General Brigham (MGB) biobank, with 123,000 subjects. However, what is lacking is the identification of biological cancer risk mechanisms in MM and translating these discoveries into cancer interception and early therapeutic interventions. This approach will allow the field to transition from a purely demographic definition of risk to a biological one. We believe that samples from the PLCO study, along with our current study cohorts, can help define the mechanistic underpinnings of the carcinogenesis process leading to MGUS/MM. Our overarching hypothesis is that defining the risk of developing MM precursors at the genomic level can more precisely identify specific populations at risk than demographic attributes and define focused strategies for early interception. In Specific Aim 1, we define the prevalence of monoclonal gammopathies in high-risk participants in the PLCO study along with MGB/PROMISE cohorts and characterize their impact on long-term health outcomes. In Specific Aim 2, we identify germline variants that predispose to developing MGUS/MM. We aim to characterize the genetic underpinnings of risk related to race and family history of disease. We expect that this approach will allow us to move past using self-reported race status for risk stratification. In Specific Aim 3, we assess the role of immune aging in developing MGUS/MM. MM is traditionally thought of as a disease of the elderly, but the risk may be better explained by the "aging tissue" of origin rather than chronological age. This approach will allow us to transition from a purely demographic definition of risk to a biological one.