Systems Biology of Bone Marrow Failure and MDS for Precision Medicine

项目总结/摘要 骨髓衰竭（BMF）的特征是血细胞生成不足，通常与 进展为骨髓增生异常综合征（MDS）或急性髓性白血病的风险增加。MDS是最 常见于老年人，这是由获得体细胞突变引起的， 骨髓和无效造血。相比之下，MDS在儿童和年轻人中更常见， 与生殖系遗传倾向和骨髓细胞减少有关。然而，综合征特征或 明确的家族史往往缺乏，所以在所有年轻患者中必须考虑遗传性BMF/MDS。的 对BMF/MDS生殖系遗传易感性的鉴定是至关重要的，因为它为医疗管理提供了信息， 为监测和早期干预提供了机会。临床护理的基本障碍 BMF/MDS患者包括致病基因的不完整目录和无法准确预测 进展为骨髓恶性肿瘤的风险。因此，本研究的目的是：目的1）提高诊断 通过在患者中鉴定新基因和变异体来评估BMF/MDS的生殖系遗传易感性 对他们来说，靶向测序和WES是非诊断性的，目的2）鉴定体细胞基因组， BMF/MDS疾病进展的转录组学和表观基因组学驱动因素， 患者的纵向管理。我们将首先关注Shwachman-Diamond综合征（SDS）， 确定新的SDS基因，并进行基因组，分子和临床的纵向，综合分析， SDS的特征，目的是了解该井中的体细胞克隆进展- 定义的临床队列。然后将该方法扩展至包括其他BMF/MDS疾病患者 在研究的最后几年。该项目汇集了一个具有以下方面专门知识的综合调查小组： 儿科和成人BMF/MDS、生殖系遗传学、体细胞基因组学、表观基因组学和转录组学。这 该项目利用不断增长的、预先存在的、带注释的BMF/MDS标本库 纵向从儿科和成人患者及其家庭成员。符合联合国的使命 RC 2，这些研究生成的临床注释数据集将随时提供给医学和 科学界通过公共平台促进BMF/MDS的科学、发现和临床护理 在儿童和年轻人中。

Project Summary/Abstract Bone marrow failure (BMF) is characterized by inadequate blood cell production and is often associated with an increased risk of progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia. MDS is most common in older adults, where it is caused by acquisition of somatic mutations that cause hypercellular marrows and ineffective hematopoiesis. By contrast, MDS in children and young adults is more commonly associated with a germline genetic predisposition and hypocellular marrows. However, syndromic features or a clear family history are often absent, so inherited BMF/MDS must be considered in all young patients. The identification of germline genetic predisposition to BMF/MDS is critical as it informs medical management and provides an opportunity for surveillance and early intervention. Fundamental barriers to clinical care of BMF/MDS patients include an incomplete catalogue of causative genes and an inability to accurately predict risk for progression to myeloid malignancy. Therefore, the aims of this study are: Aim 1) Improve the diagnosis of germline genetic predisposition to BMF/MDS through identification of novel genes and variants in patients for whom targeted sequencing and WES were non-diagnostic, and Aim 2) Identify the somatic genomic, transcriptomic, and epigenomic drivers of disease progression in BMF/MDS with the goal of informing longitudinal management of patients. We will initially focus on Shwachman-Diamond syndrome (SDS) to identify new SDS genes and conduct a longitudinal, integrated analysis of the genomic, molecular, and clinical features of SDS, with the goal of developing an understanding of somatic clonal progression within this well- defined clinical cohort. This approach will then be expanded to include patients with other BMF/MDS disorders in the latter years of the study. This project brings together an integrated team of investigators with expertise in pediatric and adult BMF/MDS, germline genetics, somatic genomics, epigenomics, and transcriptomics. This project leverages ever-growing, pre-existing, annotated repositories of BMF/MDS specimens collected longitudinally from pediatric and adult patients and their family members. Consistent with the mission of the RC2, the clinically annotated datasets generated by these studies will be readily available to the medical and scientific communities through public platforms to promote science, discovery, and clinical care for BMF/MDS in children and young adults.