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Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes
Blood Cancer Journal ( IF 12.9 ) Pub Date : 2021-11-09 , DOI: 10.1038/s41408-021-00570-9
James B Studd 1 , Alex J Cornish 1 , Phuc H Hoang 1, 2 , Philip Law 1 , Ben Kinnersley 1 , Richard Houlston 1
Affiliation  

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.



中文翻译:

急性淋巴细胞白血病亚型的癌症驱动因素和克隆动态

为了全面了解儿童急性淋巴细胞白血病 (ALL) 亚型的复合遗传驱动事件和克隆动态,我们分析了 361 名新诊断患者的肿瘤正常全基因组测序和表达数据。我们报告了结构驱动因素以及启动子中经常出现的非编码变异的鉴定。此外,我们发现组蛋白基因簇 1 的转录谱和CTCF改变的肿瘤具有超二倍体 ALL 的共同特征,表明存在“类超二倍体”亚型。所有亚型均由不同的突变过程驱动,AID 诱变仅限于ETV6-RUNX1肿瘤。亚克隆性是 ALL 普遍存在的特征,与驱动肿瘤选择和扩张的达尔文进化论一致。B 细胞发育基因(IKZF1、PAX5、ZEB2)中的驱动突变往往是克隆性的,而 RAS/RTK 突变是亚克隆性的。除了确定治疗开发的新途径外,该分析还强调靶向治疗应考虑复合突变谱和克隆性。

更新日期:2021-11-09
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