Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: A report from the Children's Oncology Group

Jinghui Zhang, Charles G. Mullighan, Richard C. Harvey, Gang Wu, Xiang Chen, Michael Edmonson, Kenneth H. Buetow, William L. Carroll, I. Ming Chen, Meenakshi Devidas, Daniela S. Gerhard, Mignon L. Loh, Gregory H. Reaman, Mary V. Relling, Bruce M. Camitta, W. Paul Bowman, Malcolm A. Smith, Cheryl L. Willman, James R. Downing, Stephen P. Hunger

Research output: Contribution to journalArticle

176 Scopus citations

Abstract

We sequenced 120 candidate genes in 187 high-risk childhood B-precursor acute lymphoblastic leukemias, 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 4 major pathways varied markedly across genetic subtypes. Among 23 leukemias expressing a BCRABL1-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 high-risk childhood B-precursor acute lymphoblastic leukemia and highlight important new therapeutic targets for selected patient subsets.

Original languageEnglish
Pages (from-to)3080-3087
Number of pages8
JournalBlood
Volume118
Issue number11
DOIs
StatePublished - 15 Sep 2011

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    Zhang, J., Mullighan, C. G., Harvey, R. C., Wu, G., Chen, X., Edmonson, M., Buetow, K. H., Carroll, W. L., Chen, I. M., Devidas, M., Gerhard, D. S., Loh, M. L., Reaman, G. H., Relling, M. V., Camitta, B. M., Bowman, W. P., Smith, M. A., Willman, C. L., Downing, J. R., & Hunger, S. P. (2011). Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: A report from the Children's Oncology Group. Blood, 118(11), 3080-3087. https://doi.org/10.1182/blood-2011-03-341412