文章：

癌症驱动因素与急性淋巴细胞白血病亚型中的克隆动态

Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

原文发布日期：2021-11-09

DOI: 10.1038/s41408-021-00570-9

类型: Article

开放获取: 是

英文摘要：

To obtain a comprehensive picture of composite genetic driver events and clonal dynamics in subtypes of paediatric acute lymphoblastic leukaemia (ALL) we analysed tumour-normal whole genome sequencing and expression data from 361 newly diagnosed patients. We report the identification of both structural drivers, as well as recurrent non-coding variation in promoters. Additionally we found the transcriptional profile of histone gene cluster 1 and CTCF altered tumours shared hallmarks of hyperdiploid ALL suggesting a ‘hyperdiploid like’ subtype. ALL subtypes are driven by distinct mutational processes with AID mutagenesis being confined to ETV6-RUNX1 tumours. Subclonality is a ubiquitous feature of ALL, consistent with Darwinian evolution driving selection and expansion of tumours. Driver mutations in B-cell developmental genes (IKZF1, PAX5, ZEB2) tend to be clonal and RAS/RTK mutations subclonal. In addition to identifying new avenues for therapeutic exploitation, this analysis highlights that targeted therapies should take into account composite mutational profile and clonality.
 

摘要翻译： 

为全面了解儿童急性淋巴细胞白血病（ALL）各亚型中的复合遗传驱动事件与克隆动态，我们分析了361例新诊断患者的肿瘤-正常组织全基因组测序及表达数据。研究发现包括结构驱动因素在内的多种驱动事件，以及在启动子区反复出现的非编码变异。此外，我们发现组蛋白基因簇1和CTCF改变肿瘤的转录谱具有与超二倍体ALL相似的特征，提示存在“类超二倍体”亚型。不同ALL亚型由特异的突变过程驱动，其中AID诱变仅局限于ETV6-RUNX1型肿瘤。亚克隆性是ALL的普遍特征，符合达尔文进化驱动肿瘤选择与扩张的规律。B细胞发育基因（IKZF1、PAX5、ZEB2）的驱动突变通常呈克隆性，而RAS/RTK通路突变多为亚克隆性。本研究不仅为治疗探索提供了新方向，同时强调靶向治疗应综合考虑复合突变谱和克隆性特征。

原文链接：

Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes