Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma

TLDR

Follicular lymphoma and diffuse large B‑cell lymphoma are the two most common non‑Hodgkin lymphomas, yet the mutations driving them have remained cryptic despite extensive research. The study aimed to identify genes with somatic mutations in B‑cell non‑Hodgkin lymphomas by sequencing tumor and matched normal DNA from 13 DLBCL and one FL cases. The authors sequenced tumor and matched normal DNA from 13 DLBCL and one FL case, analyzed RNA‑seq data from these and 113 additional NHLs to identify candidate mutated genes, and re‑sequenced tumor and matched normal DNA to confirm 109 genes with multiple somatic mutations. The analysis revealed that histone‑modifying genes are frequent mutation targets, with 32 % of DLBCL and 89 % of FL cases harboring MLL2 mutations and 11–13 % of cases carrying MEF2B mutations, indicating a previously unappreciated disruption of chromatin biology in lymphomagenesis.

Abstract

Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. 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, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis. Despite being a focus of research activity for many years, the mutations driving the two most common non-Hodgkin lymphomas — follicular lymphoma and diffuse large B-cell lymphoma — have remained cryptic. Whole genome sequencing, combined with transcriptome analysis and further resequencing of candidate genes in additional tumours, now show that histone methyltransferases and acetylases are frequently affected by mutations in these tumours. This study suggests a previously unappreciated importance of chromatin biology in lymphomagenesis.