title: Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: A Children's Oncology Group Study [corrected].
abstract: OBJECTIVE
  To identify children with acute lymphoblastic leukemia (ALL) at initial diagnosis who are at risk for inferior response to therapy by using molecular signatures.
  
  
  METHODS
  Gene expression profiles were generated from bone marrow blasts at initial diagnosis from a cohort of 99 children with National Cancer Institute-defined high-risk ALL who were treated uniformly on the Children's Oncology Group (COG) 1961 study. For prediction of early response, genes that correlated to marrow status on day 7 were identified on a training set and were validated on a test set. An additional signature was correlated with long-term outcome, and the predictive models were validated on three large, independent patient cohorts. Results We identified a 24-probe set signature that was highly predictive of day 7 marrow status on the test set (P = .0061). Pathways were identified that may play a role in early blast regression. We have also identified a 47-probe set signature (which represents 41 unique genes) that was predictive of long-term outcome in our data set as well as three large independent data sets of patients with childhood ALL who were treated on different protocols. However, we did not find sufficient evidence for the added significance of these genes and the derived predictive models when other known prognostic features, such as age, WBC, and karyotype, were included in a multivariate analysis.
  
  
  CONCLUSIONS
  Genes and pathways that play a role in early blast regression may identify patients who may be at risk for inferior responses to treatment. A fully validated predictive gene expression signature was defined for high-risk ALL that provided insight into the biologic mechanisms of treatment failure.
authors.affiliation: Division of Pediatric Hematology/Oncology, New York University Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Deepa
authors.initials: D
authors.lastname: Bhojwani
authors.forename: Huining
authors.initials: H
authors.lastname: Kang
authors.forename: Renee X
authors.initials: RX
authors.lastname: Menezes
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.forename: Harland
authors.initials: H
authors.lastname: Sather
authors.forename: Naomi P
authors.initials: NP
authors.lastname: Moskowitz
authors.forename: Dong-Joon
authors.initials: DJ
authors.lastname: Min
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Potter
authors.forename: Richard
authors.initials: R
authors.lastname: Harvey
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Nita
authors.initials: N
authors.lastname: Seibel
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Raetz
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Martin A
authors.initials: MA
authors.lastname: Horstmann
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Willman
authors.forename: William L
authors.initials: WL
authors.lastname: Carroll
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005819:Genetic Markers; D006801:Humans; D007223:Infant; D008297:Male; D015233:Models, Statistical; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics* / Q000628:therapy; D011237:Predictive Value of Tests; D012372:ROC Curve; D018570:Risk Assessment; D016896:Treatment Outcome
chemical_list: D005819:Genetic Markers
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