Background Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined. Methods We studied a cohort of 221 children with high-risk B-cell–progenitor ALL with the use of single-nucleotide–polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1–positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell–progenitor ALL. Results More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell–lineage genes, and it was similar to the signature of BCR-ABL1–positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion. Conclusions Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell–progenitor ALL.

Pediatric acute lymphoblastic leukemia (ALL) is a heterogeneous disease consisting of distinct clinical and biological subtypes that are characterized by specific chromosomal abnormalities or gene mutations. Mutation of genes encoding tyrosine kinases is uncommon in ALL, with the exception of Philadelphia chromosomepositive ALL, where the t(9,22)(q34;q11) translocation encodes the constitutively active BCR-ABL1 tyrosine kinase. We recently identified a poor prognostic subgroup of pediatric BCR-ABL1-negative ALL patients characterized by deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) and a gene expression signature similar to BCR-ABL1-positive ALL, raising the possibility of activated tyrosine kinase signaling within this leukemia subtype. Here, we report activating mutations in the Janus kinases JAK1 (n ‫؍‬ 3), JAK2 (n ‫؍‬ 16), and JAK3 (n ‫؍‬ 1) in 20 (10.7%) of 187 BCR-ABL1-negative, high-risk pediatric ALL cases. The JAK1 and JAK2 mutations involved highly conserved residues in the kinase and pseudokinase domains and resulted in constitutive JAK-STAT activation and growth factor independence of Ba/F3-EpoR cells. The presence of JAK mutations was significantly associated with alteration of IKZF1 (70% of all JAK-mutated cases and 87.5% of cases with JAK2 mutations; P ‫؍‬ 0.001) and deletion of CDKN2A/B (70% of all JAK-mutated cases and 68.9% of JAK2-mutated cases). The JAK-mutated cases had a gene expression signature similar to BCR-ABL1 pediatric ALL, and they had a poor outcome. These results suggest that inhibition of JAK signaling is a logical target for therapeutic intervention in JAK mutated ALL. IKAROS ͉ kinase ͉ mutationA cute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and despite high overall cure rates (1), ALL remains the second leading cause of cancer death in children. To improve outcome, it is necessary to identify highrisk patients at the time of diagnosis and then tailor therapy toward the genetic lesions driving their leukemia.Recent genome-wide analyses have identified common genetic alterations in childhood ALL that contribute to leukemogenesis (2, 3). To identify genetic lesions predictive of poor outcome in childhood ALL, we recently performed genomewide analysis of DNA copy number alterations, transcriptional profiling, and gene resequencing in a cohort of 221 children with B progenitor ALL predicted to be at high risk for relapse based on age and presentation leukocyte count (4). These patients were treated on the Children's Oncology Group P9906 trial by using an augmented reinduction/reconsolidation strategy (''Berlin-Frankfurt-Münster'' regimen) (5, 6). This cohort excluded patients with known good (ETV6-RUNX1 or trisomies 4 and 10) or very poor (hypodiploid, BCR-ABL1) risk sentinel genetic lesions, and it represents Ϸ12% of noninfant B precursor ALL cases (Table S1). Alteration of the lymphoid transcription factor IKZF1 (IKAROS) was associated with poor outcome and a leukemic cell gene expression signature highly similar to that of BCR-ABL1...

Purpose:To conduct a comprehensive analysis of radiologist-made assessments of glioblastoma (GBM) tumor size and composition by using a community-developed controlled terminology of magnetic resonance (MR) imaging visual features as they relate to genetic alterations, gene expression class, and patient survival. Materials and Methods:Because all study patients had been previously deidentified by the Cancer Genome Atlas (TCGA), a publicly available data set that contains no linkage to patient identifiers and that is HIPAA compliant, no institutional review board approval was required. Presurgical MR images of 75 patients with GBM with genetic data in the TCGA portal were rated by three neuroradiologists for size, location, and tumor morphology by using a standardized feature set. Interrater agreements were analyzed by using the Krippendorff a statistic and intraclass correlation coefficient. Associations between survival, tumor size, and morphology were determined by using multivariate Cox regression models; associations between imaging features and genomics were studied by using the Fisher exact test. Results:Interrater analysis showed significant agreement in terms of contrast material enhancement, nonenhancement, necrosis, edema, and size variables. Contrast-enhanced tumor volume and longest axis length of tumor were strongly associated with poor survival (respectively, hazard ratio: 8.84, P = .0253, and hazard ratio: 1.02, P = .00973), even after adjusting for Karnofsky performance score (P = .0208). Proneural class GBM had significantly lower levels of contrast enhancement (P = .02) than other subtypes, while mesenchymal GBM showed lower levels of nonenhanced tumor (P , .01). Conclusion:This analysis demonstrates a method for consistent image feature annotation capable of reproducibly characterizing brain tumors; this study shows that radiologists' estimations of macroscopic imaging features can be combined with genetic alterations and gene expression subtypes to provide deeper insight to the underlying biologic properties of GBM subsets.q RSNA, 2013

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Purpose Esophageal squamous cell carcinoma (ESCC) is an aggressive tumor with poor prognosis. Understanding molecular changes in ESCC will enable identification of molecular subtypes and provide potential targets for early detection and therapy. Experimental Design We followed up a previous array study with additional discovery and confirmatory studies in new ESCC cases using alternative methods. We profiled global gene expression for discovery and confirmation, and validated selected dysregulated genes with additional RNA and protein studies. Results A total of 159 genes showed differences with extreme statistical significance (P