Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes.
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Authors
Studd, JB
Cornish, AJ
Hoang, PH
Law, P
Kinnersley, B
Houlston, R
Cornish, AJ
Hoang, PH
Law, P
Kinnersley, B
Houlston, R
Document Type
Journal Article
Date
2021-11-09
Date Accepted
2021-10-27
Abstract
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.
Citation
Blood cancer journal, 2021, 11 (11), pp. 177 - ?
Source Title
Publisher
SPRINGERNATURE
ISSN
2044-5385
eISSN
2044-5385
2044-5385
2044-5385
Collections
Research Team
Cancer Genomics