Project 3: Early detection and prevention of MM progression

项目摘要 多发性骨髓瘤（MM）是一种恶性浆细胞肿瘤，可导致贫血、高钙血症、肾功能衰竭、骨髓增生异常综合征和骨髓增生异常综合征。 功能不全和骨病变。它之前是一个共同的良性单克隆浆细胞扩增称为 未确定意义的单克隆丙种球蛋白病（MGUS），其起始事件与 毫米这些包括复发性免疫球蛋白基因易位和超二倍体。第三种临床 实体在这两者之间，郁积型多发性骨髓瘤（SMM），其中有更广泛的 浆细胞扩张较MGUS明显，但未见MM的恶性特征。该项目的重点是 利用遗传学更精确地区分良性和恶性浆细胞， MM的定义。我们假设次级遗传事件的积累标志着从 从良性到恶性这些事件涉及许多癌症常见的一些途径： MYC/MAX、MAPK（NRAS、KRAS、BRAF、FGFR 3、PTPN 11、NF 1）、NF κ B（TRAF 3、TRAF 2、CYLD、BIRC 2/3、 MAPK 3 K14）、TP 53/MDM 2、RB 1/CDKN 2C、其他（DIS 3、FAM 46 C）。其中一条通路在 >95%的MM和<5%的MGUS，我们假设它们单独或组合可用于 定义恶性浆细胞。也有越来越多的证据表明肿瘤微环境的作用， SMM的进展和最近的克隆性造血与炎症增加有关， 我们将使用下一代测序技术来鉴定克隆造血， 描述MGUS、SMM和MM患者中存在的遗传事件，并将其与 临床过程我们将在一个独立的SMM患者队列中验证我们的发现， 前瞻性随机临床试验。最终，我们希望遗传学的定义将允许早期 检测并及时治疗MM，从而预防MM的恶性后果，以及 延长患者的生存期。

PROJECT SUMMARY Multiple myeloma (MM) is a malignant plasma cell neoplasm leading to anemia, hypercalcemia, renal insufficiency and bone lesions. It is preceded by a common benign monoclonal plasma cell expansion called monoclonal gammopathy of undetermined significance (MGUS) that shares the same initiating events seen in MM. These include recurrent immunoglobulin gene translocations, and hyperdiploidy. There is a third clinical entity in between these two, smoldering multiple myeloma (SMM), in which there has been more extensive plasma cell expansion than MGUS, but the malignant features of MM are not seen. This project is focused on using genetics to more precisely demarcate benign from malignant plasma cells and develop a patho-genetic definition of MM. We hypothesize that an accumulation of secondary genetic events mark the progression from a benign to malignant state. These events involve a handful of pathways common to many cancers: MYC/MAX, MAPK (NRAS, KRAS, BRAF, FGFR3, PTPN11, NF1), NFKB (TRAF3, TRAF2, CYLD, BIRC2/3, MAPK3K14), TP53/MDM2, RB1/CDKN2C, Others (DIS3, FAM46C). One of these pathways is dysregulated in >95% of MM and <5% of MGUS, and we postulate that individually or in combination they can be used to define malignant plasma cells. There is also increasing evidence of a role of the tumor microenvironment in progression of SMM, and recently clonal hematopoiesis has been associated with increased inflammation, and more rapid progression of MM. We will use next generation sequencing to identify clonal hematopoiesis, and to characterize the genetic events present in patients with MGUS, SMM and MM, and correlate these with the clinical course. We will validate our findings in an independent cohort of patients with SMM enrolled on prospective randomized clinical trials. Ultimately, we hope that a genetic definition will allow both the early detection and prompt treatment of MM, resulting in the prevention of the malignant consequences of MM, and prolonged survival for patients.