Relevance of ID3-TCF3-CCND3 pathway mutations in pediatric aggressive B-cell lymphoma treated according to the non-Hodgkin Lymphoma Berlin-Frankfurt-Münster protocols

Abstract

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 <i>MYC</i> 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. <i>ID3, TCF3</i> and <i>CCND3</i> are potential drivers of Burkitt lymphomagenesis. In the study herein, frequency and clinical relevance of mutations in <i>ID3, TCF3</i> and <i>CCND3</i> 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% (<i>ID3</i>), 13% (<i>TCF3</i>) and 36% (<i>CCND3</i>) in Burkitt lymphoma (including Burkitt leukemia). <i>ID3</i> and <i>CCND3</i> mutations were associated with more advanced stages of the disease in <i>MYC</i> rearrangement positive Burkitt lymphoma. In conclusion, <i>ID3-TCF3-CCND3</i> pathway genes are mutated in more than 88% of <i>MYC</i>-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.