Genetic and Epigenetic Factors Driving Primary Mediastinal B-Cell Lymphoma Pathogenesis and Outcome

Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive lymphoma affecting predominantly young female patients. Here we report a large-scale genetic investigation of 490 PMBCL cases using paired whole-genome (n=14), whole-exome (n=78) and targeted sequencing (n=465) unraveling a complex genomic landscape. Genetic lesions in epigenetic/chromatin modifiers were found in >90% of cases, with ZNF217 being among the most frequently mutated genes. In vitro, ZNF217 knockout led to global changes in chromatin accessibility interfering with binding motifs for crucial lymphoma-associated transcription factors resulting in disturbed expression of interferon-responsive and inflammation-associated genes. Among genetic lesions with prognostic information, CD58 mutations were identified to be independently associated with shorter survival. In contrast, mutated DUSP2 indicated longer survival with no further benefit from treatment intensification in this very-low risk patient group. Concluding, these data revealed a previously underappreciated role of chromatin modifiers, identified novel treatment targets and provides a basis for precision medicine approaches in PMBCL.