Acute leukemia is a particularly problematic collection of hematological cancers, and, while somewhat rare, the survival rate of patients is typically abysmal without bone marrow transplantation. Furthermore, traditional chemotherapies used as standard-of-care for patients cause significant side effects. Understanding the evolution of leukemia to identify novel targets and, therefore, drug treatment regimens is a significant medical need. Genomic rearrangements and other structural variations (SVs) have long been known to be causative and pathogenic in multiple types of cancer, including leukemia. These SVs may be involved in cancer initiation, progression, clonal evolution, and drug resistance, and a better understanding of SVs from individual patients may help guide therapeutic options. Here, we show the utilization of optical genome mapping (OGM) to detect known and novel SVs in the samples of patients with leukemia. Importantly, this technology provides an unprecedented level of granularity and quantitation unavailable to other current techniques and allows for the unbiased detection of novel SVs, which may be relevant to disease pathogenesis and/or drug resistance. Coupled with the chemosensitivities of these samples to FDA-approved oncology drugs, we show how an impartial integrative analysis of these diverse datasets can be used to associate the detected genomic rearrangements with multiple drug sensitivity profiles. Indeed, an insertion in the geneMUSKis shown to be associated with increased sensitivity to the clinically relevant agent Idarubicin, while partial tandem duplication events in theKMT2Agene are related to the efficacy of another frontline treatment, Cytarabine.
急性白血病是一类尤为棘手的血液系统恶性肿瘤，尽管相对罕见，但若不进行骨髓移植，患者的生存率通常极低。此外，作为患者标准治疗的传统化疗方案常引发显著的副作用。因此，深入理解白血病的演变过程以识别新的治疗靶点并制定相应的药物治疗方案，已成为一项重要的临床需求。长期以来，基因组重排及其他结构变异已被证实是包括白血病在内的多种癌症的致病因素。这些结构变异可能参与癌症的发生、进展、克隆演化及耐药过程，对个体患者的结构变异进行更深入的理解有助于指导治疗选择。本研究展示了利用光学基因组图谱技术在白血病患者样本中检测已知及新型结构变异的方法。重要的是，该技术提供了当前其他方法无法达到的精细度和定量水平，并能够无偏倚地检测可能与疾病发病机制和/或耐药性相关的新型结构变异。结合这些样本对美国食品药品监督管理局批准的肿瘤药物的化疗敏感性数据，我们展示了如何通过对这些多样化数据集进行客观整合分析，将检测到的基因组重排与多种药物敏感性特征相关联。研究证实，MUSK基因的插入变异与对临床相关药物伊达比星的敏感性增强相关，而KMT2A基因的部分串联重复事件则与另一种一线治疗药物阿糖胞苷的疗效存在关联。
肿瘤(癌症)患者之家