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

Abstract

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.

Benign and malignant tumors in Rubinstein–Taybi syndrome

“…Since somatic CREBBP mutation is a very frequent early event in follicular B‐cell lymphoma and diffuse large B‐cell lymphoma (Lohr et al, 2012; Morin et al, 2011; Pasqualucci et al, 2011; Zhang et al, 2011), this case was studied for somatic CREBBP alterations (Stevens et al, 2017). A somatic CREBBP mutation on one allele was found (His1438Asp, variant allele frequency [VAF] 25%), while the known germline mutation ( CREBBP c.4837delG) was found in only 6% of sequence reads.…”

“…Mutations in CREBBP and EP300 have been demonstrated in various benign and malignant tumors, including in up to 40% of diffuse large cell B‐cell lymphoma (DLBCL) and follicular lymphoma cases (Lohr et al, 2012; Morin et al, 2011; Pasqualucci et al, 2011; Zhang et al, 2011). A specific type of acute myeloid leukemia is associated with a chromosomal translocation involving CREBBP (Rozman et al, 2004).…”

BCL2 mutations in diffuse large B-cell lymphoma

“…19 Briefly, paired end reads, obtained by sequencing both ends of each DNA fragment of an RNA-seq library, were aligned to the human reference genome (hg18) and exon junction sequences (to allow correct alignment of reads spanning exons) using the Burrows-Wheeler Aligner. 25 Single nucleotide variants were identified with SNVMix software (http://compbio.bccrc.ca/software/snvmix/).…”

“…16 Using the transcriptome sequencing method RNA-seq 17 in 89 DLBCL samples, we recently identified genomic changes that drive the pathogenesis of adult DLBCL. 18,19 The most commonly mutated gene, mutated in 33/89 transcriptomes (37%) was BCL2. 19 The aims of the current study were to determine the frequency and distribution of BCL2 mutations in DLBCL in a large number of cases, assess the relationship between gene mutation and BCL2 protein expression or BCL2 translocation, and determine the impact of mutations on immunohistochemical detection of protein expression and clinical outcome.…”

“…18,19 The most commonly mutated gene, mutated in 33/89 transcriptomes (37%) was BCL2. 19 The aims of the current study were to determine the frequency and distribution of BCL2 mutations in DLBCL in a large number of cases, assess the relationship between gene mutation and BCL2 protein expression or BCL2 translocation, and determine the impact of mutations on immunohistochemical detection of protein expression and clinical outcome. We also tested whether BCL2 mutations are specific to DLBCL by sequencing the BCL2 gene in other lymphoma subtypes with and without BCL2 translocations.…”