The genomic landscape of pediatric acute lymphoblastic leukemia

Mullighan Lab

Mullighan Lab

Mar 23, 2022


Whole Genome Sequencing
Whole Exome Sequencing
SNP Array

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. In this genomepaint view mutations for each gene are displayed by chromosome location and ALL subtype. The viewer is encouraged to enter the HUGO gene name of interest of chromosome cooordinates in the text box defaulted to TP53 coordinates in order to explore the data set.

Here, using whole-genome, exome and transcriptome sequencing of 2,754 childhood patients with ALL, we find that, despite a generally low mutation burden, ALL cases harbor a median of four putative somatic driver alterations per sample, with 376 putative driver genes identified varying in prevalence across ALL subtypes. Most samples harbor at least one rare gene alteration, including 70 putative cancer driver genes associated with ubiquitination, SUMOylation, noncoding transcripts and other functions. In hyperdiploid B-ALL, chromosomal gains are acquired early and synchronously before ultraviolet-induced mutation. By contrast, ultraviolet-induced mutations precede chromosomal gains in B-ALL cases with intrachromosomal amplification of chromosome 21. We also demonstrate the prognostic significance of genetic alterations within subtypes. Intriguingly, DUX4- and KMT2A-rearranged subtypes separate into CEBPA/FLT3- or NFATC4-expressing subgroups with potential clinical implications. Together, these results deepen understanding of the ALL genomic landscape and associated outcomes.

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