Genetic Landscape of Acute Myeloid Leukemia (AML) in Older Patients

近年来，新一代测序（NGS）技术的发展极大地促进了我们对AML分子发病机制的理解。然而，大多数关于AML基因组谱的研究都来自年轻的成年患者。从对老年患者的小型研究中，越来越多的证据表明老年患者的（epi）遗传特征与年轻患者有很大不同。拟议项目的具体目标是：使用靶向DNA测序，在至少1 000名老年AML患者的队列中评估突变谱，确定共同突变和相互排斥的模式，并完善老年AML的基因组分类;鉴定低甲基化剂治疗的预后和预测因素，和建立适用于老年患者的新的遗传风险分类;表观遗传签名的生成;使用新的Oxford Nanopore技术检测新的融合基因并评估改变的剪接的作用的转录谱分析（RNA-seq）;使用单细胞测序来鉴定对靶向治疗的药物反应的异质性。对于该项目，我们有一个来自前瞻性随机临床试验的独特生物库，以及来自我们大型AMLSG生物注册的样本。

In recent years, the development of next-generation sequencing (NGS) techniques have greatly advanced our understanding of the molecular pathogenesis of AML. However, most studies on the genomic profiling of AML stem from younger adult patients. From smaller studies in older patients there is increasing evidence that the (epi)genetic profile in older patients greatly differs from that of younger patients. The specific aims of the proposed project are: Evaluation of the mutational spectrum, identification of patterns of co-mutations and mutual exclusivities in a cohort of at least 1,000 older AML patients using targeted DNA sequencing, and refinement of the genomic classification of older AML; identification of prognostic and predictive factors to treatment with hypomethylating agents, and establishment of a new genetic risk classification applicable for older patients; generation of epigenetic signatures; transcriptional profiling (RNA-seq) using the novel Oxford Nanopore technology for detecting novel fusion genes and evaluating the role of altered splicing; use of single-cell sequencing to identify heterogeneity of drug response to targeted therapies. For the project we have a unique biobank from a prospective, randomized clinical trial as well as samples from our large AMLSG BiO Registry available.