We sequenced 120 candidate genes in 187 high-risk childhood B-precursor acute lymphoblastic leukemias (HR B-ALL), the largest pediatric cancer genome sequencing effort reported to date. Integrated analysis of 179 validated somatic sequence mutations with genome-wide copy number alterations and gene expression profiles revealed a high frequency of recurrent somatic alterations in key signaling pathways including B cell development/differentiation (68% of cases), the TP53/RB tumor suppressor pathway (54%), Ras signaling (50%), and Janus kinases (11%). Recurrent mutations were also found in ETV6 (6 cases), TBL1XR1 (3), CREBBP (3), MUC4 (2), ASMTL (2) and ADARB2 (2). The frequency of mutations within the four major pathways varied markedly across genetic subtypes. Among 23 leukemias expressing a BCR-ABL1-like gene expression profile, 96% had somatic alterations in B cell development/differentiation, 57% in JAK, and 52% in both pathways, whereas only 9% had RAS pathway mutations. In contrast, 21 cases defined by a distinct gene expression profile coupled with focal ERG deletion rarely had B cell development/differentiation or JAK kinase alterations, but had a high frequency (62%) of RAS signaling pathway mutations. These data extend the range of genes that are recurrently mutated in HR B-ALL and highlight important new therapeutic targets for selected patient subsets.
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