A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study
By M. L. Boer, M. V. Slegtenhorst, R. X. Menezes, M. Cheok, J. Buijs-Gladdines, S. T. Peters, L. Zutven, H. Beverloo, P. Spek, Gaby Escherich and 5 more. The Lancet Oncology, 2009
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SUMMARY Background In childhood acute lymphoblastic leukemia (ALL) genetic subtypes are recognized that determine the risk-group for further treatment. However, 25% of precursor BALL are currently genetically unclassified and have an intermediate prognosis. The present study used genome-wide strategies to reveal new biological insights and advance the prognostic classification of childhood ALL. Methods A classifier based on gene expression in ALL cells from 190 newly diagnosed pediatric cases was constructed using a double-loop cross-validation method and next, was validated on an independent cohort of 107 newly diagnosed pediatric ALL cases. Hierarchical cluster analysis using classifying gene probe sets then revealed a novel ALL subtype for which underlying genetic abnormalities were characterized by comparative genomic hybridization-arrays and molecular cytogenetics. Findings The prediction accuracy of the classifier was median 90% in the discovery cohort and 87.9% in the independent validation cohort. A significant part of the currently genetically unclassified cases clustered with BCR-ABL-positive cases in both the discovery and validation cohort. These BCR-ABL-like cases represent 15–20% of ALL cases and have a highly unfavorable outcome (5-year disease-free survival 59.5%, 95%CI: 37.1%–81.9%) compared to other precursor B-ALL cases (84.4%, 95%CI: 76.8%–92.1%; P=0.012), similar to the poor prognosis of BCR-ABL-positive ALL (51.9%, 95%CI: 23.1%–80.6%), as was confirmed in the validation cohort. Further genetic studies revealed that the BCR-ABL-like subtype is characterized by a high frequency of deletions in genes involved in B-cell development (82%), including IKAROS, E2A, EBF1, PAX5 and VPREB1, compared to other ALL cases (36%, p=0.0002). BCR-ABL-like leukemic cells were median >70-times resistant to L-asparaginase (p=0.001) and 1.6-times more resistant to daunorubicin (p=0.017) compared to other precursor B-ALL cases whereas the toxicity of prednisolone and vincristine did not significantly differ. Interpretation Classification by gene expression profiling identified a novel subtype of ALL not detected by current diagnostic procedures but which comprises the largest group of patients with a high-risk of treatment failure. New treatment strategies are needed to improve outcome for this novel high-risk subtype of ALL. Funding Dutch Cancer Society, Sophia Foundation for Medical Research, Pediatric Oncology Foundation Rotterdam, Center of Medical Systems Biology of the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research, American National Institute of Health, American National Cancer Institute and American Lebanese Syrian Associated Charities.
Subfields: Hematology, Oncology, Public Health, Environmental and Occupational Health
View Paper: https://www.semanticscholar.org/paper/03928049fdedc5b5850edbd3a214af1baa6f2809
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Citations in the corpus
- Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration. (2015, background): “In 2009, two groups of investigators using a different gene expression profiling approach identified a subtype of high-risk B ALL that lacked a known chromosomal rearrangement but exhibited a gene expression profile similar to that of Ph-positive ALL with deletions and, less commonly, sequence mutat”
- Biology, risk stratification, and therapy of pediatric acute leukemias: an update. (2011, background): “Interestingly, there is a high-risk subgroup of BCR-ABL1– negative ALL that is characterized by IKZF1 deletion and has a genetic profile similar to that of cases with BCR-ABL1 fusion.(46,47) In search of activated tyrosine kinase signaling in this leukemic subtype, Mullighan et al(48) identified act”
- Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia (2012, background): “…alteration is a hallmark of Philadelphia chromosome (Ph+) ALL with BCRABL1 fusion (Mullighan et al., 2008; Iacobucci et al., 2009) and is also associated with poor outcome in both BCR-ABL1positive and BCR-ABL1-negative ALL (Den Boer et al., 2009; Martinelli et al., 2009; Mullighan et al., 2009b).”
- Effect of separate sampling on classification accuracy (2014, neutral): “Numbering Article Classification problem/source of data 1 [1] Ovarian 2 [10] SRBCT 3 [20] Prediction of outcome in pediatric ALL 4 [15] DLBCL outcome prediction 5 [17] Breast cancer classification 6 [19] Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas 7 [3] Prediction of t”