Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: A Children's Oncology Group Study [corrected].

TY - JOUR

T1 - Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: A Children's Oncology Group Study [corrected].

AU - Bhojwani, Deepa

AU - Kang, Huining

AU - Menezes, Renee X

AU - Yang, Wenjian

AU - Sather, Harland

AU - Moskowitz, Naomi P

AU - Min, Dong-Joon

AU - Potter, Jeffrey W

AU - Harvey, Richard

AU - Hunger, Stephen P

AU - Seibel, Nita

AU - Raetz, Elizabeth A

AU - Pieters, Rob

AU - Horstmann, Martin A

AU - Relling, Mary V

AU - den Boer, Monique L

AU - Willman, Cheryl L

AU - Carroll, William L

AU - Children's Oncology Group Study

PY - 2008/9/20

Y1 - 2008/9/20

N2 - PURPOSE: To identify children with acute lymphoblastic leukemia (ALL) at initial diagnosis who are at risk for inferior response to therapy by using molecular signatures. PATIENTS AND 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. CONCLUSION: 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.

AB - PURPOSE: To identify children with acute lymphoblastic leukemia (ALL) at initial diagnosis who are at risk for inferior response to therapy by using molecular signatures. PATIENTS AND 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. CONCLUSION: 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.

KW - Adolescent

KW - Child

KW - Child, Preschool

KW - Female

KW - Gene Expression Profiling

KW - Gene Expression Regulation, Neoplastic

KW - Genetic Markers

KW - Humans

KW - Infant

KW - Male

KW - Models, Statistical

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma

KW - Predictive Value of Tests

KW - ROC Curve

KW - Risk Assessment

KW - Treatment Outcome

U2 - 10.1200/JCO.2007.14.4519

DO - 10.1200/JCO.2007.14.4519

M3 - SCORING: Journal article

C2 - 18802149

VL - 26

SP - 4376

EP - 4384

JO - J CLIN ONCOL

JF - J CLIN ONCOL

SN - 0732-183X

IS - 27

M1 - 27

ER -