Gene expression signatures predictive of early response and outcome in high-risk childhood acute lymphoblastic leukemia: A Children's oncology group study on behalf of the Dutch Childhood Oncology Group and the German Cooperative Study Group for childhood acute lymphoblastic leukemia

被引:85
作者
Bhojwani, Deepa
Kang, Huining
Menezes, Renee X.
Yang, Wenjian
Sather, Harland
Moskowitz, Naomi P.
Min, Dong-Joon
Potter, Jeffrey W.
Harvey, Richard
Hunger, Stephen P.
Seibel, Nita
Raetz, Elizabeth A.
Pieters, Rob
Horstmann, Martin A.
Relling, Mary V.
den Boer, Monique L.
Willman, Cheryl L.
Carroll, William L. [1 ]
机构
[1] NYU, Ctr Canc, Div Pediat Hematol Oncol, Sch Med, New York, NY 10016 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1200/JCO.2007.14.4519
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
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收藏
页码:4376 / 4384
页数:9
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