A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.
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A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study. / Den, Boer; Monique, L; Slegtenhorst, van; Marjon, [Unbekannt]; Menezes, De; Renée, X; Cheok, [Unbekannt]; Meyling, H; Buijs-Gladdines, [Unbekannt]; Jessica, G C A M; Peters, [Unbekannt]; Susan, T C J M; Zutven, Van; Laura, J C M; Beverloo, [Unbekannt]; Berna, H; Spek, Van der; Peter, J; Escherich, Gabriele; Gaby, [Unbekannt]; Horstmann, Martin; Martin, A; Janka-Schaub, Gritta; Gritta, E; Kamps, [Unbekannt]; Willem, A; Evans, [Unbekannt]; William, E; Pieters, [Unbekannt]; Rob, [Unbekannt].
In: LANCET ONCOL, Vol. 10, No. 2, 2, 01.02.2009, p. 125-134.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome-wide classification study.
AU - Den, Boer
AU - Monique, L
AU - Slegtenhorst, van
AU - Marjon, [Unbekannt]
AU - Menezes, De
AU - Renée, X
AU - Cheok, [Unbekannt]
AU - Meyling, H
AU - Buijs-Gladdines, [Unbekannt]
AU - Jessica, G C A M
AU - Peters, [Unbekannt]
AU - Susan, T C J M
AU - Zutven, Van
AU - Laura, J C M
AU - Beverloo, [Unbekannt]
AU - Berna, H
AU - Spek, Van der
AU - Peter, J
AU - Escherich, Gabriele
AU - Gaby, [Unbekannt]
AU - Horstmann, Martin
AU - Martin, A
AU - Janka-Schaub, Gritta
AU - Gritta, E
AU - Kamps, [Unbekannt]
AU - Willem, A
AU - Evans, [Unbekannt]
AU - William, E
AU - Pieters, [Unbekannt]
AU - Rob, [Unbekannt]
PY - 2009/2/1
Y1 - 2009/2/1
N2 - BACKGROUND: Genetic subtypes of acute lymphoblastic leukaemia (ALL) are used to determine risk and treatment in children. 25% of precursor B-ALL cases are genetically unclassified and have intermediate prognosis. We aimed to use a genome-wide study to improve prognostic classification of ALL in children. METHODS: We constructed a classifier based on gene expression in 190 children with newly diagnosed ALL (German Cooperative ALL [COALL] discovery cohort) by use of double-loop cross-validation and validated this in an independent cohort of 107 newly diagnosed patients (Dutch Childhood Oncology Group [DCOG] independent validation cohort). Hierarchical cluster analysis with classifying gene-probe sets revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics. FINDINGS: Our classifier predicted ALL subtype with a median accuracy of 90.0% (IQR 88.3-91.7) in the discovery cohort and correctly identified 94 of 107 patients (accuracy 87.9%) in the independent validation cohort. Without our classifier, 44 children in the COALL cohort and 33 children in the DCOG cohort would have been classified as B-other. However, hierarchical clustering showed that many of these genetically unclassified cases clustered with BCR-ABL1-positive cases: 30 (19%) of 154 children with precursor B-ALL in the COALL cohort and 14 (15%) of 92 children with precursor B-ALL in the DCOG cohort had this BCR-ABL1-like disease. In the COALL cohort, these patients had unfavourable outcome (5-year disease-free survival 59.5%, 95% CI 37.1-81.9) compared with patients with other precursor B-ALL (84.4%, 76.8-92.1%; p=0.012), a prognosis similar to that of patients with BCR-ABL1-positive ALL (51.9%, 23.1-80.6%). In the DCOG cohort, the prognosis of BCR-ABL1-like disease (57.1%, 31.2-83.1%) was worse than that of other precursor B-ALL (79.2%, 70.2-88.3%; p=0.026), and similar to that of BCR-ABL1-positive ALL (32.5%, 2.3-62.7%). 36 (82%) of the patients with BCR-ABL1-like disease had deletions in genes involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1; only nine (36%) of 25 patients with B-other ALL had deletions in these genes (p=0.0002). Compared with other precursor B-ALL cells, BCR-ABL1-like cells were 73 times more resistant to L-asparaginase (p=0.001) and 1.6 times more resistant to daunorubicin (p=0.017), but toxicity of prednisolone and vincristine did not differ. INTERPRETATION: New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL. FUNDING: Dutch Cancer Society, Sophia Foundation for Medical Research, Paediatric Oncology Foundation Rotterdam, Centre 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.
AB - BACKGROUND: Genetic subtypes of acute lymphoblastic leukaemia (ALL) are used to determine risk and treatment in children. 25% of precursor B-ALL cases are genetically unclassified and have intermediate prognosis. We aimed to use a genome-wide study to improve prognostic classification of ALL in children. METHODS: We constructed a classifier based on gene expression in 190 children with newly diagnosed ALL (German Cooperative ALL [COALL] discovery cohort) by use of double-loop cross-validation and validated this in an independent cohort of 107 newly diagnosed patients (Dutch Childhood Oncology Group [DCOG] independent validation cohort). Hierarchical cluster analysis with classifying gene-probe sets revealed a new ALL subtype, the underlying genetic abnormalities of which were characterised by comparative genomic hybridisation-arrays and molecular cytogenetics. FINDINGS: Our classifier predicted ALL subtype with a median accuracy of 90.0% (IQR 88.3-91.7) in the discovery cohort and correctly identified 94 of 107 patients (accuracy 87.9%) in the independent validation cohort. Without our classifier, 44 children in the COALL cohort and 33 children in the DCOG cohort would have been classified as B-other. However, hierarchical clustering showed that many of these genetically unclassified cases clustered with BCR-ABL1-positive cases: 30 (19%) of 154 children with precursor B-ALL in the COALL cohort and 14 (15%) of 92 children with precursor B-ALL in the DCOG cohort had this BCR-ABL1-like disease. In the COALL cohort, these patients had unfavourable outcome (5-year disease-free survival 59.5%, 95% CI 37.1-81.9) compared with patients with other precursor B-ALL (84.4%, 76.8-92.1%; p=0.012), a prognosis similar to that of patients with BCR-ABL1-positive ALL (51.9%, 23.1-80.6%). In the DCOG cohort, the prognosis of BCR-ABL1-like disease (57.1%, 31.2-83.1%) was worse than that of other precursor B-ALL (79.2%, 70.2-88.3%; p=0.026), and similar to that of BCR-ABL1-positive ALL (32.5%, 2.3-62.7%). 36 (82%) of the patients with BCR-ABL1-like disease had deletions in genes involved in B-cell development, including IKZF1, TCF3, EBF1, PAX5, and VPREB1; only nine (36%) of 25 patients with B-other ALL had deletions in these genes (p=0.0002). Compared with other precursor B-ALL cells, BCR-ABL1-like cells were 73 times more resistant to L-asparaginase (p=0.001) and 1.6 times more resistant to daunorubicin (p=0.017), but toxicity of prednisolone and vincristine did not differ. INTERPRETATION: New treatment strategies are needed to improve outcome for this newly identified high-risk subtype of ALL. FUNDING: Dutch Cancer Society, Sophia Foundation for Medical Research, Paediatric Oncology Foundation Rotterdam, Centre 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.
KW - Child
KW - Child, Preschool
KW - Cluster Analysis
KW - Comparative Genomic Hybridization
KW - Gene Expression
KW - Gene Expression Profiling
KW - Genes, abl
KW - Humans
KW - Kaplan-Meier Estimate
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma
KW - Predictive Value of Tests
KW - Prognosis
KW - Treatment Outcome
U2 - 10.1016/S1470-2045(08)70339-5
DO - 10.1016/S1470-2045(08)70339-5
M3 - SCORING: Journal article
C2 - 19138562
VL - 10
SP - 125
EP - 134
JO - LANCET ONCOL
JF - LANCET ONCOL
SN - 1470-2045
IS - 2
M1 - 2
ER -