title: Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group.
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.
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Zhang
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Richard C
authors.initials: RC
authors.lastname: Harvey
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Xiang
authors.initials: X
authors.lastname: Chen
authors.forename: Michael
authors.initials: M
authors.lastname: Edmonson
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Buetow
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
authors.forename: I-Ming
authors.initials: IM
authors.lastname: Chen
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Gerhard
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Reaman
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Camitta
authors.forename: W Paul
authors.initials: WP
authors.lastname: Bowman
authors.forename: Malcolm A
authors.initials: MA
authors.lastname: Smith
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: James R
authors.initials: JR
authors.lastname: Downing
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
mesh_terms: D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008495:Medical Oncology / Q000458:organization & administration; D009154:Mutation / Q000502:physiology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D012955:Societies, Medical