Molecular prediction of myeloma in African Americans

非裔美国人骨髓瘤的分子预测

• 批准号: 10468436
• 负责人: Irene M. Ghobrial
• 金额: $ 89.25万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-12 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468436
• 关键词: African American; African American population; Age; Aging; Biological; Black race; Chronology; Cohort Studies; DNA; Data; Development; Diagnosis; Disease; Early Diagnosis; Elderly; Family history of; Frequencies; Genetic; Genomics; Goals; Health; Hematologic Neoplasms; Hematopoietic Neoplasms; Immune; Immune system; Individual; Intercept; MALDI-TOF Mass Spectrometry; Malignant Neoplasms; Measures; Molecular; Monoclonal Gammapathies; Monoclonal gammopathy of uncertain significance; Morbidity - disease rate; Multiple Myeloma; Organ; Outcome; Participant; Patient Self-Report; Patients; Peripheral Blood Mononuclear Cell; Persons; Population; Populations at Risk; Prevalence; Prevention; Process; Progression-Free Survivals; Prospective cohort study; Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial; Race; Recording of previous events; Risk; Risk Factors; Role; Sampling; Serum; Source; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; T cell receptor repertoire sequencing; T-Lymphocyte; T-cell diversity; Therapeutic Intervention; Time; Tissues; Translating; Variant; base; biobank; cancer risk; carcinogenesis; case control; cohort; gammopathy; genome sequencing; genomic signature; high risk; high risk population; improved; novel; risk stratification; screening; sex; tool; whole genome

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.

概括 多发性骨髓瘤（mm）几乎总是先于早期前体疾病： 不确定的意义（MGU）和闷烧的骨髓瘤（SMM）。大约3％的人口> 50年 有mgus，使其成为非常常见的前体状况。有家人的人的风险高2-3倍 MM的历史或黑人/非裔美国人（AA）。在这里，我们认为，而不是按种族定义风险 仅家庭历史，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。经过 筛查MGU的高危人群，可以为患者制定早期预防和拦截策略 谁会从早期的治疗干预措施中受益。我们的初步数据确定了MGU的患病率 高风险人群中约有13％；数据来自两个来源：我们的前瞻性队列研究（承诺 研究），即筛选30,000名参与者在发育中的MM和大型回顾性组织银行 研究，大众杨百翰（MGB）生物库，有123,000名受试者。但是，缺少的是 MM中生物癌风险机制的鉴定并将这些发现转化为癌症 拦截和早期治疗干预措施。这种方法将使该领域从纯粹的 人口统计学对生物学风险的定义。我们认为，PLCO研究的样本以及我们的 当前的研究队列可以帮助定义致癌过程的机械基础，导致 mgus/mm。我们的总体假设是，在确定在 基因组水平比人口属性更精确地识别有风险的特定人群， 为早期拦截定义集中的策略。在特定目标1中，我们定义了单克隆的患病率 PLCO研究的高风险参与者的伽马病以及MGB/Promise队列的表征 它们对长期健康结果的影响。在特定目标2中，我们确定了易感性的种系变异 开发mgus/mm。我们旨在表征与种族和家庭有关的风险遗传基础 疾病史。我们希望这种方法将使我们能够使用自我报告的种族身份来过去 风险分层。在特定目标3中，我们评估免疫衰老在开发MGU/mm中的作用。 MM是 传统上认为是老年人的疾病，但风险可以通过 起源而不是年代年龄。 这种方法将使我们从纯粹的人口统计学定义过渡 生物学的风险。