Characterizing the genomic landscape in pediatric B-cell lymphomas reveals the timing of tumorigenesis events

Abstract

Understanding the genomic landscape and genetic subtypes of B-cell lymphomas is critical for developing improved targeted therapies and for increasing the survival of relapse cases. Prior reports have investigated the occurrence of mutations in adult and pediatric lymphoma patients and have described enrichment of genomic alterations in subtypes. Determining when these alterations occurred can improve our understanding of their pathogenicity and increase our understanding of the disease. Here we analyzed WGS data of a cohort of pediatric B-cell non-Hodgkin lymphoma cases to further investigate the genomic landscape, the underlying mutational processes, and the timing of the genomic events in these lymphoma types. We observed recurrently mutated driver genes, and recurrent structural variants and copy number alterations. In DLBCL samples, mutational hotspots in B-cell driver genes induced by aberrant somatic hypermutation and an elevated mutational load were identified. In Burkitt samples, we found characteristic translocations involving the MYC gene and the immunoglobulin heavy chain locus. These translocations were negative for recombination signal sequence motifs, indicating that they were not induced by aberrant VDJ recombination of the heavy chain, but are instead induced by aberrant class switch recombination. Additionally, we found that driver mutations occurred relatively early in the development of the tumor and copy number alterations had a relatively late timing. Based on our findings, we propose a general model for the relative timing of events in the tumorigenesis of B-cell non-Hodgkin lymphoma. In this model, a mature B-cell harboring a driver mutation gains additional genomic alterations driving the tumor as a result of aberrant processes in the maturation of the B-cell receptor. Our model sheds light on the initiation and progression of these lymphoma subtypes and provides a framework for guiding future research in unraveling the complex molecular mechanisms underlying their development.