Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

Abstract

To obtain a comprehensive picture of composite genetic drivers 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 novel coding and structural drivers as well as recurrent non-coding variation in promoters and cis -regulatory regions. 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.