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.

Figure 1

Genes with recurrent mutations identified in 187 ALL patients.

Figure 2

An integrated view of somatic CNA and sequence mutation in genes with recurrent sequence mutations across the 187 patients. Samples are displayed in columns and grouped by their corresponding ROSE clusters. Genes are shown in rows grouped by their corresponding pathways. Somatic sequence mutations are marked in orange unless they occur with a somatic deletion (which is shown in cyan). Multiple mutations within a single gene are labeled “x.” Somatic deletions and amplifications are shown in blue and red, and the shades indicate the level of CNAs

Figure 3

Distribution of cases and mutations according to ROSE clustering subgroups. (A) Distribution of the 8 patient subgroups identified by unsupervised clustering of gene expression profiles using the ROSE method. The subgroups, labeled contiguously from R1 to R8, include 2 subgroups associated with known recurrent cytogenetic abnormalities: R1 with translocations of MLL and R2 with TCF3-PBX1 fusion, 1 subgroup that lacks sentinel abnormality (R7), 1 subgroup with good outcome (R6), and 1 subgroup with poor outcome (R8). (B) Somatic alteration profiles incorporating both sequence mutations and CNAs in TP53/RB1 signaling, B-cell development, Ras signaling, and JAK signaling pathways. The frequency of patients exhibiting mutations in these 4 pathways among the 8 ROSE gene-expression subgroups differs significantly from the null hypothesis (ie, that the mutations are randomly distributed across all 8 subgroups) with a P value of 9.38 × 10⁻⁷, 3.38 × 10⁻⁸, 1.53 × 10⁻⁷, and 2.16 × 10⁻¹⁰ for TP53/RB1 signaling, B-cell development, Ras signaling, and JAK signaling, respectively by χ² test.

Figure 4

Somatic mutations in ETV6. (A) Distribution of somatic sequence mutations in ETV6. The N-terminal pointed (PNT) is involved in protein-protein interactions with itself and other proteins, whereas the C-terminal ETS domain (red) is involved in DNA binding. (B) Single and double mutations in ETV6. The genomic region in display is chromosome 12:11 619 584–12 112 117 (genome build hg18). Each row represents a sample with somatic alterations. Gray lines indicate deletions; and black lines, homozygous deletions. Sequence mutations are shown as vertical black boxes.