Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

James B. Studd,Alex J. Cornish,Philip Law,Richard Houlston,Phuc H. Hoang,Ben Kinnersley

doi:10.1038/s41408-021-00570-9

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.

Highlights

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer, with around 80% of ALL cases derived from B-cell precursors (BCP-ALL) [1]
The most common chromosome-arm level aberrations were loss of 9p and gain of 21q, both occurring in 8% of cases (Supplementary Fig. 4). 21q gain occurred preferentially in hypodiploid tumours (Q = 0.10), whereas 9p loss was most frequent in TCF3-PBX1 translocated tumours (Q = 0.19), and (Supplementary Fig. 5a and 5b)
Since iAMP21 tumours are defined by RUNX1 copy number, we examined the distribution of structural variants (SVs) on chromosome 21, finding no clustering evident (Supplementary Fig. 7)

Summary

Introduction

Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer, with around 80% of ALL cases derived from B-cell precursors (BCP-ALL) [1]. The disease is characterised by initiating genetic lesions resulting in characteristic patterns of chromosomal gain (hyperdiploidy), loss (hypodiploidy) or the formation of fusion genes. Recurrent fusions include t(12;21) ETV6RUNX1, t(1;19) TCF3-PBX1 and t(9;22) BCR-ABL1 [1]. Copy number changes in RUNX1, caused by intra-chromosomal amplification (iAMP21), and ERG deletion, have more recently been recognised as initiating events [2, 3]. For example patients with hyperdiploid ALL have 5-year survival rate (5YSR) of > 90% [7]. In comparison around 60% of iAMP21 positive ALL will relapse resulting in 5YSR of only 29% [5]

Methods

Results

Conclusion