Relevance of ID3-TCF3-CCND3 pathway mutations in pediatric aggressive B-cell lymphoma treated according to the non-Hodgkin Lymphoma Berlin-Frankfurt-Münster protocols
Marius Rohde,
Bettina R. Bonn,
Martin Zimmermann,
Jonas Lange,
Anja Möricke,
Wolfram Klapper,
Ilske Oschlies,
Monika Szczepanowski,
Inga Nagel,
Martin Schrappe,
MMML-MYC-SYS Project,
ICGC MMML-Seq Project,
Markus Loeffler,
Reiner Siebert,
Alfred Reiter,
Birgit Burkhardt
Affiliations
Marius Rohde
Department of Pediatric Hematology and Oncology, Justus-Liebig-University Giessen, Germany
Bettina R. Bonn
Department of Pediatric Hematology and Oncology, Justus-Liebig-University Giessen, Germany
Martin Zimmermann
Department of Pediatric Hematology and Oncology, Justus-Liebig-University Giessen, Germany
Jonas Lange
Pediatric Hematology and Oncology, University Hospital Münster, Germany;Translational Oncology, Department of Medicine A, University Hospital Münster; Cluster of Excellence EXC 1003, Cells in Motion, Münster, Germany
Anja Möricke
Pediatric Hematology and Oncology, University Medical Center Schleswig-Holstein, Campus Kiel, Germany
Wolfram Klapper
Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrecht University, Kiel, Germany
Ilske Oschlies
Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrecht University, Kiel, Germany
Monika Szczepanowski
Department of Pathology, Hematopathology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel/Christian-Albrecht University, Kiel, Germany
Inga Nagel
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Germany
Martin Schrappe
Pediatric Hematology and Oncology, University Medical Center Schleswig-Holstein, Campus Kiel, Germany
MMML-MYC-SYS Project
Institute for Medical Informatics Statistics and Epidemiology, University Leipzig, Germany
ICGC MMML-Seq Project
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Germany;Institute of Human Genetics, University of Ulm and University Medical Center Ulm, Germany
Markus Loeffler
Institute for Medical Informatics Statistics and Epidemiology, University Leipzig, Germany
Reiner Siebert
Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Germany;Institute of Human Genetics, University of Ulm and University Medical Center Ulm, Germany
Alfred Reiter
Department of Pediatric Hematology and Oncology, Justus-Liebig-University Giessen, Germany
Birgit Burkhardt
Pediatric Hematology and Oncology, University Hospital Münster, Germany
Mature B-cell non-Hodgkin lymphoma is the most common subtype of non-Hodgkin lymphoma in childhood and adolescence. B-cell non-Hodgkin lymphomas are further classified into histological subtypes, with Burkitt lymphoma and Diffuse large B-cell lymphoma being the most common subgroups in pediatric patients. Translocations involving the MYC oncogene are known as relevant but not sufficient for Burkitt lymphoma pathogenesis. Recently published large-scale next-generation sequencing studies unveiled sets of additional recurrently mutated genes in samples of pediatric and adult B-cell non-Hodgkin lymphoma patients. ID3, TCF3 and CCND3 are potential drivers of Burkitt lymphomagenesis. In the study herein, frequency and clinical relevance of mutations in ID3, TCF3 and CCND3 were analyzed within a well-defined cohort of 84 uniformly diagnosed and treated pediatric B-cell non-Hodgkin lymphoma patients of the Berlin-Frankfurt-Münster group. Mutation frequency was 78% (ID3), 13% (TCF3) and 36% (CCND3) in Burkitt lymphoma (including Burkitt leukemia). ID3 and CCND3 mutations were associated with more advanced stages of the disease in MYC rearrangement positive Burkitt lymphoma. In conclusion, ID3-TCF3-CCND3 pathway genes are mutated in more than 88% of MYC-rearranged pediatric B-cell non-Hodgkin lymphoma and the pathway may represent a highly relevant second hit of Burkitt lymphoma pathogenesis, especially in children and adolescents.
