Faculty Collaboration Database

Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. Blood 2011 Sep 15;118(11):3080-7

Date

06/18/2011

Pubmed ID

21680795

Pubmed Central ID

PMC3175785

DOI

10.1182/blood-2011-03-341412

Scopus ID

2-s2.0-80052922387 (requires institutional sign-in at Scopus site)   216 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 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 high-risk childhood B-precursor acute lymphoblastic leukemia and highlight important new therapeutic targets for selected patient subsets.

Author List

Zhang J, Mullighan CG, Harvey RC, Wu G, Chen X, Edmonson M, Buetow KH, Carroll WL, Chen IM, Devidas M, Gerhard DS, Loh ML, Reaman GH, Relling MV, Camitta BM, Bowman WP, Smith MA, Willman CL, Downing JR, Hunger SP

MESH terms used to index this publication - Major topics in bold

Child
Child, Preschool
Cohort Studies
DNA Mutational Analysis
Female
Gene Frequency
Genes, ras
Humans
Infant
Male
Medical Oncology
Mutation
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Risk Factors
Signal Transduction
Societies, Medical