Abstract
Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL). Using RNA sequencing, we find in-frame fusion genes in 127 (65%) cases, including 27 novel fusions. We describe a subtype characterized by recurrent IGH-DUX4 or ERG-DUX4 fusions, representing 4% of cases, leading to overexpression of DUX4 and frequently co-occurring with intragenic ERG deletions. Furthermore, we identify a subtype characterized by an ETV6-RUNX1-like gene-expression profile and coexisting ETV6 and IKZF1 alterations. Thus, this study provides a detailed overview of fusion genes in paediatric BCP ALL and adds new pathogenetic insights, which may improve risk stratification and provide therapeutic options for this disease.
Highlights
Fusion genes are potent driver mutations in cancer
We report that gene fusions are present in 65% of B-cell precursor acute lymphoblastic leukaemia (BCP ALL), and identify several new fusions and two novel subtypes; one characterized by recurrent IGH-double homeobox 4 (DUX4) or ERG-DUX4 fusions and one characterized by an ETV6-RUNX1-like gene-expression profile, and coexisting ETV6 and IKZF1 alterations
Using RNA sequencing (RNA-seq), we identified an in-frame fusion gene in 127/195 (65%) BCP ALL cases and out-of-frame fusions in 20/195 (10%) cases (Fig. 1 and Supplementary Data 2–4)
Summary
Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL). The mutational landscapes of BCP ALL subtypes defined by ETV6-RUNX1, TCF3-PBX1, TCF3-HLF, high hyperdiploidy (51–67 chromosomes), hypodiploidy (o45 chromosomes) or MLL ( known as KMT2A) rearrangements have been delineated using high-resolution sequencing techniques[9,10,11,12,13]. These studies have almost exclusively been performed at the DNA level and no large-scale characterization of the gene-fusion landscape in paediatric BCP ALL has been reported to date. We report that gene fusions are present in 65% of BCP ALL, and identify several new fusions and two novel subtypes; one characterized by recurrent IGH-DUX4 or ERG-DUX4 fusions and one characterized by an ETV6-RUNX1-like gene-expression profile, and coexisting ETV6 and IKZF1 alterations
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