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Gene Expression Signatures Predictive of Early Response and Outcome in High-Risk Childhood Acute Lymphoblastic Leukemia: A Children's Oncology Group Study

Deepa Bhojwani, Huining Kang, Renee X. Menezes, Wenjian Yang, Harland Sather, Naomi P. Moskowitz, Dong-Joon Min, Jeffrey W. Potter, Richard Harvey, Stephen P. Hunger, Nita Seibel, Elizabeth A. Raetz, Rob Pieters, Martin A. Horstmann, Mary V. Relling, Monique L. den Boer, Cheryl L. Willman, William L. Carroll

From the New York University Cancer Institute and Division of Pediatric Hematology/Oncology, New York University School of Medicine; and Department of Pediatrics, Mount Sinai School of Medicine, New York, NY; Cancer Research and Treatment Center, University of New Mexico and Sandia National Laboratories, Albuquerque, NM; the Department of Paediatric Oncology/Haematology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam; and Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands; Department of Pharmaceutical Sciences, Colleges of Medicine and Pharmacy, University of Tennessee, Memphis, TN; University of Southern California and Children's Oncology Group, Arcadia, CA; Department of Pediatrics, University of Florida College of Medicine and University of Florida Shands Cancer Center, Gainesville, FL; Department of Hematology and Oncology, Children's National Medical Center, George Washington University School of Medicine and Public Health, Washington, DC; and Research Institute and Clinic of Pediatric Oncology, University Medical Center, Hamburg, Germany

Corresponding author: William L. Carroll, MD, Division of Pediatric Hematology Oncology, New York University Cancer Center and School of Medicine, 550 First Avenue, New York, NY 10016; William.carroll{at}nyumc.org

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.

Supported by Grants No. U01 CA114762, CA21765 (W.Y. and M.V.R.), and CA51001 (W.Y. and M.V.R.) from the National Cancer Institute; Director's Challenge Grant No. U01 CA88361 (C.L.W., W.L.C.); by the Penelope London Foundation; the Friedman Fund for Childhood Leukemia; the Walter Family Pediatric Leukemia Fund; the Garrett B. Smith Foundation (N.P.M.); the Pediatric Cancer Foundation; the Dutch Cancer Society and the Pediatric Oncology Foundation of Rotterdam (M.L.D., R.X.M., and R.P.); the Center of Medical Systems Biology, established by the Netherlands Genomics Initiative/Netherlands Organization for Scientific Research (R.X.M.); Grants No. U01 GM61393 and U01 GM61374 from the National Institutes of Health National Institute of General Medical Sciences Pharmacogenetics Research Network and Database (W.Y. and M.V.R.); and the American-Lebanese-Syrian Associated Charities (W.Y. and M.V.R.).

R.P. reports on behalf of the Dutch Childhood Oncology Group, The Hague, the Netherlands; M.A.H. reports on behalf of the German Cooperative Study Group for Childhood ALL, Hamburg, Germany.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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