Abstract
Intrachromosomal amplification of chromosome 21 (iAMP21) identifies a high-risk subtype of acute lymphoblastic leukaemia (ALL), requiring intensive treatment to reduce their relapse risk. Improved understanding of the genomic landscape of iAMP21-ALL will ascertain whether these patients may benefit from targeted therapy. We performed whole-exome sequencing of eight iAMP21-ALL samples. The mutation rate was dramatically disparate between cases (average 24.9, range 5–51) and a large number of novel variants were identified, including frequent mutation of the RAS/MEK/ERK pathway. Targeted sequencing of a larger cohort revealed that 60% (25/42) of diagnostic iAMP21-ALL samples harboured 42 distinct RAS pathway mutations. High sequencing coverage demonstrated heterogeneity in the form of multiple RAS pathway mutations within the same sample and diverse variant allele frequencies (VAFs) (2–52%), similar to other subtypes of ALL. Constitutive RAS pathway activation was observed in iAMP21 samples that harboured mutations in the predominant clone (⩾35% VAF). Viable iAMP21 cells from primary xenografts showed reduced viability in response to the MEK1/2 inhibitor, selumetinib, in vitro. As clonal (⩾35% VAF) mutations were detected in 26% (11/42) of iAMP21-ALL, this evidence of response to RAS pathway inhibitors may offer the possibility to introduce targeted therapy to improve therapeutic efficacy in these high-risk patients.
Highlights
Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer
Whole-exome sequencing (WES) and genomic analysis of Intrachromosomal amplification of chromosome 21 (iAMP21)-ALL WES identified 199 somatic mutations in 8 iAMP21-ALL samples that were predicted to be deleterious to protein function (Supplementary Table 4)
1825 from 5 to 51, and on average the mutated allele was represented in 33% of reads; this value was designated the variant allele frequency (VAF)
Summary
Acute lymphoblastic leukaemia (ALL) is the most common childhood cancer. Chromosomal abnormalities define subgroups of ALL, often related to distinct clinical features and outcome.[1]. Recurrent copy number abnormalities (CNAs) and somatic mutations have been identified in genes within key cell-signalling pathways.[2,3,4,5] The involvement of different pathways is ALL subgroup specific, and their clinical and biological significance is related to the genomic background on which they occur.[3,6,7] A range of inhibitors are being developed to target key signalling pathways, and experimental studies have shown response to these inhibitors in primary ALL cells.[4,8,9] understanding the biological and clinical role of such abnormalities in individual ALL subgroups may have future therapeutic benefit.[10]
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