Integrated genomic, transcriptional and epigenomic analyses in germinal center-cell lymphomas link the mutation landscape with differential DNA methylation in Burkitt lymphoma

Biologically and clinically diverse B-cell neoplasms, including Burkitt, follicular and diffuse large B-cell lymphoma, show features of germinal center (GC) B-cells. Here we present a comprehensive analysis of the epigenetic landscape of GC-B-cell lymphomas using whole genome bisulfite sequencing paired with genome and transcriptome sequencing from 29 primary tumor samples and four normal GC-B-cell samples. All lymphomas studied showed extensive genome-wide methylation losses as well as intragenic regions where DNA methylation levels were strongly correlated with expression of associated genes. Pathway analysis revealed that these intragenic regions were enriched in signaling networks differentially activated in Burkitt and follicular lymphomas and affected regulatory mechanisms deregulated by recurrent mutations in a large fraction of Burkitt lymphomas (including the ID3/TCF3 complex, the SWI/SNF remodeling complex and the inhibitory G?I signaling pathway). Taken together, these results provide a global picture of Burkitt lymphoma pathomechanism and demonstrate a tight connection between epigenetic regulation and other levels of regulatory control in these tumors.EGA study EGAS00001001067