Frequent mutation of histone modifying genes in non-Hodgkin lymphoma

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). To identify genes with mutations in B-cell NHL we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase. 11.4% of DLBCL and 13.4% of FL cases had somatic mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis thus suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis.