A multi-omics analysis of transformed nodal marginal zone lymphoma

Background:The mechanisms underlying transformation of nodal marginal zone lymphoma (NMZL) into diffuse large B-cell lymphoma (DLBCL) remain unclear.Patients and methods: We applied a multi-omics approach to analyze genomic and transcriptomic changes in 17 NMZL and 15 transformed NMZL (tNMZL), using whole genome sequencing, targeted sequencing, and gene expression profiling.Results: We included 15 nodal DLBCL cases as controls.The median fraction of genome altered was significantly higher in tNMZL compared with NMZL [0.23 (range 0.14-0.67),versus 0.11 (range 3.1 10 -4 -0.34), P < 0.01].The median number of mutations was not different, with 3 (range 0-10) in NMZL, compared with 6.5 (range 2-16) (P = 0.10) in tNMZL.In contrast, the median number of pathogenic mutations in nodal DLBCL (8.5, range 5-17) was significantly higher compared with NMZL (P < 0.01) and tNMZL (P = 0.04).The most frequently mutated genes in tNMZL included B2M (30%) and MEF2B (30%).Protein expression of BCL6, a downstream target of MEF2B, was observed more frequently in tNMZL (73%), compared with NMZL (6%) (P < 0.01).Overall, six genes were differentially expressed between NMZL and tNMZL. Conclusion:In conclusion, our study indicates that transformation of NMZL is characterized by a slight increase in genomic complexity and a gain of BCL6 expression.