An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions.
Oncogenic subtypes in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are used for risk stratification. However, a significant number of BCP-ALL patients are still genetically unassigned. Using array-comparative genomic hybridization in a selected BCP-ALL cohort, we characterized a recurrent V(D)J-mediated intragenic deletion of the ERG gene (ERG(del)). A breakpoint-specific PCR assay was designed and used to screen an independent non-selected cohort of 897 children aged 1-17 years treated for BCP-ALL in the EORTC-CLG 58951 trial. ERG(del) was found in 29/897 patients (3.2%) and was mutually exclusive of known classifying genetic lesions, suggesting that it characterized a distinct leukemia entity. ERG(del) was associated with higher age (median 7.0 vs. 4.0 years, P=0.004), aberrant CD2 expression (43.5% vs. 3.7%, P<0.001) and frequent IKZF1 Δ4-7 deletions (37.9% vs. 5.3%, P<0.001). However, ERG(del) patients had a very good outcome, with an 8-year event-free survival (8-y EFS) and an 8-year overall survival of 86.4% and 95.6%, respectively, suggesting that the IKZF1 deletion had no impact on prognosis in this genetic subtype. Accordingly, within patients with an IKZF1 Δ4-7 deletion, those with ERG(del) had a better outcome (8-y EFS: 85.7% vs. 51.3%; hazard ratio: 0.16; 95% confidence interval: 0.02-1.20; P=0.04). These findings have implications for further stratification including IKZF1 status.
1] U944 INSERM and Hematology laboratory, St-Louis Hospital, APHP, Paris, France [2] Department of Genetics, Robert Debré Hospital, APHP, Paris, France [3] Hematology University Institute, University Paris-Diderot, Paris, France.
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Clappier
1] U944 INSERM and Hematology laboratory, St-Louis Hospital, APHP, Paris, France [2] Department of Pediatric Hematology, St-Louis Hospital, APHP, Paris, France.
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Auclerc
EORTC Headquarters, Brussels, Belgium.
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Rapion
Molecular Hematology Laboratory, UZ Brussels, Brussels, Belgium.
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Bakkus
Department of Genetics, Robert Debré Hospital, APHP, Paris, France.
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Caye
Department of Genetics, Robert Debré Hospital, APHP, Paris, France.
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Khemiri
Department of Genetics, Robert Debré Hospital, APHP, Paris, France.
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Giroux
U944 INSERM and Hematology laboratory, St-Louis Hospital, APHP, Paris, France.
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Hernandez
Molecular Hematology Laboratory, UZ Brussels, Brussels, Belgium.
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Kabongo
MRC-Holland, Amsterdam, The Netherlands.
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Savola
Department of Pediatric Hematology, St-Louis Hospital, APHP, Paris, France.
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Leblanc
Department of Pediatric Hematology, Robert-Debré Hospital, APHP, Paris, France.
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Yakouben
Department of Pediatric Onco-Hematology, University Hospital Purpan, Toulouse, France.
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Plat
Department of Pediatrics, Portuguese Oncology Institute, Porto, Portugal.
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Costa
Department of Pediatric Onco-Hematology, Children's University Hospital Reine Fabiola, Brussels, Belgium.
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Ferster
Hematology Laboratory, IHOP, Lyon, France.
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Girard
Hematology Laboratory, Robert Debré Hospital, APHP, Paris, France.
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Fenneteau
1] U944 INSERM and Hematology laboratory, St-Louis Hospital, APHP, Paris, France [2] Hematology University Institute, University Paris-Diderot, Paris, France.
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Cayuela
1] U944 INSERM and Hematology laboratory, St-Louis Hospital, APHP, Paris, France [2] Hematology University Institute, University Paris-Diderot, Paris, France.
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Sigaux
Hematology Laboratory, University Hospital Purpan, Toulouse, France.
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Dastugue
EORTC Headquarters, Brussels, Belgium.
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Suciu
Department of Pediatric Hematology-Oncology, Ghent University Hospital, Ghent, Belgium.
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Benoit
Department of Pediatric Hematology, IHOP and Claude Bernard University, Lyon, France.
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Bertrand
1] U944 INSERM and Hematology laboratory, St-Louis Hospital, APHP, Paris, France [2] Hematology University Institute, University Paris-Diderot, Paris, France.
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Soulier
1] Department of Genetics, Robert Debré Hospital, APHP, Paris, France [2] Hematology University Institute, University Paris-Diderot, Paris, France.
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Cavé
D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D017931:DNA Primers; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics*; D007223:Infant; D008297:Male; D016133:Polymerase Chain Reaction; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG
D017931:DNA Primers; C072312:ERG protein, human; C497239:IKZF1 protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D051740:Ikaros Transcription Factor