Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia.
In the search for genes that define critical steps of relapse in pediatric T-cell acute lymphoblastic leukemia (T-ALL) and can serve as prognostic markers, we performed targeted sequencing of 313 leukemia-related genes in 214 patients: 67 samples collected at the time of relapse and 147 at initial diagnosis. As relapse-specific genetic events, we identified activating mutations in NT5C2 (P=0.0001, Fisher's exact test), inactivation of TP53 (P=0.0007, Fisher's exact test) and duplication of chr17:q11.2-24.3 (P=0.0068, Fisher's exact test) in 32/67 of T-ALL relapse samples. Alterations of TP53 were frequently homozygous events, which significantly correlated with higher rates of copy number alterations in other genes compared with wild-type TP53 (P=0.0004, Mann-Whitney's test). We subsequently focused on mutations with prognostic impact and identified genes governing DNA integrity (TP53, n=8; USP7, n=4; MSH6, n=4), having key roles in the RAS signaling pathway (KRAS, NRAS, n=8), as well as IL7R (n=4) and CNOT3 (n=4) to be exclusively mutated in fatal relapses. These markers recognize 24/49 patients with a second event. In 17 of these patients with mostly refractory relapse and dire need for efficient treatment, we identified candidate targets for personalized therapy with p53 reactivating compounds, MEK inhibitors or JAK/STAT-inhibitors that may be incorporated in future treatment strategies.
Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.
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Richter-Pechańska
Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.|German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
J B
JB
Kunz
Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.
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J
Hof
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
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M
Zimmermann
Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.|European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.
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0000-0001-5773-5620
T
Rausch
Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.|German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
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Bandapalli
Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.
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E
Orlova
Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.|University of Padua, Padua, Italy.
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G
Scapinello
Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.
J C
JC
Sagi
Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
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M
Stanulla
Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
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M
Schrappe
Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
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G
Cario
Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.
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0000-0001-6335-3274
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Kirschner-Schwabe
Department of Pediatric Oncology/Hematology, Charité Universitätsmedizin Berlin, Berlin, Germany.
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C
Eckert
European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.
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0000-0002-0352-2547
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Benes
Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.|European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.
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JO
Korbel
Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.
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MU
Muckenthaler
Department of Pediatric Oncology, Hematology, and Immunology, University of Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany.|German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany.
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Kulozik
D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D012307:Risk Factors