Molecular prediction of myeloma in African Americans

总结 多发性骨髓瘤（MM）几乎总是伴随着早期前驱疾病： 未确定显著性（MGUS）和阴燃性骨髓瘤（SMM）。约3%的人口>50岁 有MGUS，使其成为一个非常常见的前兆条件。有家庭的人风险高2-3倍 MM病史或黑人/非裔美国人（AA）。在这里，我们认为，与其按种族定义风险， 如果仅限于家族史，我们将风险定义为特定的基因组特征，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， 能从早期治疗中获益我们的初步数据确定了MGUS的患病率， 高风险人群中约13%;数据来自两个来源：我们的前瞻性队列研究（PROMISE 该研究筛选了30，000名有患MM风险的参与者，并进行了一项大型回顾性组织库 研究，马萨诸塞州总布里格姆（MGB）生物银行，与123,000名受试者。然而，缺少的是 确定MM中的生物学癌症风险机制，并将这些发现转化为癌症 拦截和早期治疗干预。这种方法将使该领域从纯粹的 从人口学定义的风险到生物学定义的风险。我们相信PLCO研究的样本，沿着我们的 目前的研究队列，可以帮助确定致癌过程的机制基础， MGUS/MM。我们的总体假设是，定义MM前体的风险， 基因组水平可以比人口统计学属性更精确地识别特定的风险人群， 确定早期拦截的重点战略。在具体目标1中，我们定义了单克隆抗体的患病率， 在PLCO研究沿着MGB/PROMISE队列的高风险参与者中， 对长期健康结果的影响。在具体目标2中，我们确定了易患以下疾病的种系变异： 发展MGUS/MM。我们的目标是描述与种族和家庭有关的风险的遗传基础 疾病史。我们希望这种方法将允许我们过去使用自我报告的种族状态， 危险分层在具体目标3中，我们评估了免疫老化在发生MGUS/MM中的作用。 传统上被认为是老年人的疾病，但这种风险可能更好地解释为“老化组织”， 而不是年龄。 这种方法将使我们能够从纯粹的人口定义过渡到 对生物的威胁

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.