Recurrent targets of aberrant somatic hypermutation in lymphoma

Abstract

Somatic hypermutation (SHM) in the variable region of immunoglobulin genes (IGV) naturally occurs in a narrow window of B cell development to provide high-affinity antibodies. However, SHM can also aberrantly target proto-oncogenes and cause genome instability. The role of aberrant SHM (aSHM) has been widely studied in various non-Hodgkin's lymphoma particularly in diffuse large B-cell lymphoma (DLBCL). Although, it has been speculated that aSHM targets a wide range of genome loci so far only twelve genes have been identified as targets of aSHM through the targeted sequencing of selected genes. A genome-wide study aiming at identifying a comprehensive set of aSHM targets recurrently occurring in DLBCL has not been previously undertaken. Here, we present a comprehensive assessment of the somatic hypermutated genes in DLBCL identified through an analysis of genomic and transcriptome data derived from 40 DLBCL patients. Our analysis verifies that there are indeed many genes that are recurrently affected by aSHM. In particular, we have identified 32 novel targets that show same or higher level of aSHM activity than genes previously reported. Amongst these novel targets, 22 genes showed a significant correlation between mRNA abundance and aSHM.

Mutational and structural analysis of diffuse large B-cell lymphoma using whole-genome sequencing

“…We observed nonrandom patterns of SNV distribution across the genomes with particular enrichment near transcription start sites, an observation that is consistent with aberrant somatic hypermutation (aSHM; catalyzed by AID), which we have described elsewhere. 22 Beyond this local variability in mutation rates, we also detected distinct mutational patterns and sequence contexts across individual patients. There was a broad range of overall somatic mutation load among the sequenced genomes, with the total number of candidate somatic SNVs detected per case ranging from 1165 to 48 385.…”

Exome sequencing reveals novel mutation targets in diffuse large B-cell lymphomas derived from Chinese patients

“…21,23,49 Additionally, the DTX1 locus was recently proposed to constitute a target of aberrant SHM in DLBCL, but no protein-coding alterations were reported. 34 In addition to being a transcriptional target of Notch, 50 DTX1 was also demonstrated to negatively regulate Notch activity at the protein level, thus constituting a potential inhibitory feedback mechanism of the Notch pathway. 36 Notch signaling is an evolutionary conserved pathway that exerts distinct effects on cellular development in particular contexts, being able to provide both survival and growth arrest signals to cells.…”

“…Of note, TMSB4X was recently described as a target of aberrant SHM in DLBCL. 34 However, no details were provided on whether SHM affected the coding regions of the gene. Mutations in LYN have been reported in low frequencies in endometrial, breast, and lung malignancies (http://cancer.sanger.ac.uk/cosmic/ gene/analysis?ln5LYN#histo) but, to the best of our knowledge, have not yet been described for DLBCL.…”

Mutation of cancer driverMLL2results in transcription stress and genome instability

“…In other cell types and contexts, other mutation sites in other genes might well be prevalent. Interestingly, whole-tumor genome sequencing data indicate that hot spots of mutation are enriched in the transcribed region within the first 2 kb after the TSS, starting to rise immediately upon the transit from transcriptional initiation to active elongation (Khodabakhshi et al 2012). We suggest that MLL2 is particularly important to suppress such mutation, at least partly by reducing replication problems resulting from clashes with RNAPII undergoing transcription stress, and that, in its absence, cells therefore gain a "mutator" phenotype (Loeb 2001), which is particularly damaging because it preferentially targets active genes.…”