de Smith Adam J, Ojha Juhi, Francis Stephen S, Sanders Erica, Endicott Alyson A, Hansen Helen M, Smirnov Ivan, Termuhlen Amanda M, Walsh Kyle M, Metayer Catherine, Wiemels Joseph L
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
Division of Neuroepidemiology, Department of Neurological Surgery, University of California San Francisco, San Francisco, California, United States of America.
Oncotarget. 2016 Nov 8;7(45):72733-72745. doi: 10.18632/oncotarget.12238.
High hyperdiploidy (HD), the most common cytogenetic subtype of B-cell acute lymphoblastic leukemia (B-ALL), is largely curable but significant treatment-related morbidity warrants investigating the biology and identifying novel drug targets. Targeted deep-sequencing of 538 cancer-relevant genes was performed in 57 HD-ALL patients lacking overt KRAS and NRAS hotspot mutations and lacking common B-ALL deletions to enrich for discovery of novel driver genes. One-third of patients harbored damaging mutations in epigenetic regulatory genes, including the putative novel driver DOT1L (n=4). Receptor tyrosine kinase (RTK)/Ras/MAPK signaling pathway mutations were found in two-thirds of patients, including novel mutations in ROS1, which mediates phosphorylation of the PTPN11-encoded protein SHP2. Mutations in FLT3 significantly co-occurred with DOT1L (p=0.04), suggesting functional cooperation in leukemogenesis. We detected an extraordinary level of tumor heterogeneity, with microclonal (mutant allele fraction <0.10) KRAS, NRAS, FLT3, and/or PTPN11 hotspot mutations evident in 31/57 (54.4%) patients. Multiple KRAS and NRAS codon 12 and 13 microclonal mutations significantly co-occurred within tumor samples (p=4.8x10-4), suggesting ongoing formation of and selection for Ras-activating mutations. Future work is required to investigate whether tumor microheterogeneity impacts clinical outcome and to elucidate the functional consequences of epigenetic dysregulation in HD-ALL, potentially leading to novel therapeutic approaches.
高超二倍体（HD）是B细胞急性淋巴细胞白血病（B-ALL）最常见的细胞遗传学亚型，虽大多可治愈，但显著的治疗相关发病率促使人们研究其生物学特性并确定新的药物靶点。对57例HD-ALL患者进行了538个癌症相关基因的靶向深度测序，这些患者无明显的KRAS和NRAS热点突变，也无常见的B-ALL缺失，以富集发现新的驱动基因。三分之一的患者在表观遗传调控基因中存在有害突变，包括推测的新驱动基因DOT1L（n = 4）。三分之二的患者存在受体酪氨酸激酶（RTK）/Ras/MAPK信号通路突变，包括ROS1中的新突变，ROS1介导PTPN11编码蛋白SHP2的磷酸化。FLT3突变与DOT1L显著共发生（p = 0.04），提示在白血病发生过程中存在功能协同作用。我们检测到了极高水平的肿瘤异质性，31/57（54.4%）的患者中存在微克隆（突变等位基因分数<0.10）KRAS、NRAS、FLT3和/或PTPN11热点突变。肿瘤样本中多个KRAS和NRAS密码子12和13微克隆突变显著共发生（p = 4.8x10-4），提示Ras激活突变正在持续形成并被选择。未来需要开展工作来研究肿瘤微异质性是否影响临床结局，并阐明HD-ALL中表观遗传失调的功能后果，这可能会带来新的治疗方法。
