High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma

Abstract

Using high-resolution genomic microarray analysis, a distinct genomic pro-file was defined in 114 samples from patients with splenic marginal zonelymphoma (SMZL). Deletion or uniparental disomy of chromosome 7qwere detected in 42 of 114 (37%) SMZLs but in only nine of 170 (5%)mature B-cell lymphomas (P<0 00001). The presence of unmutatedIGHV, genomic complexity, 17p13-TP53deletion and 8q-MYCgain, butnot 7q deletion, correlated with shorter overall survival of SMZL patients.Mapping studies narrowed down a commonly deleted region of 2 7Mbin7q32.1-q32.2 spanning a region between theSND1andCOPG2genes.High-throughput sequencing analysis of the 7q32-deleted segment did notidentify biallelic deletions/insertions or clear pathogenic gene mutations,but detected six nucleotide changes inIRF5(n=2),TMEM209(n=2),CALU(n=1) andZC3HC1(n=1) not found in healthy individuals.Comparative expression analysis found a fourfold down-regulation ofIRF5gene in lymphomas with 7q32 deletionversusnon-deleted tumours(P=0 032). Ectopic expression of IRF5 in marginal-zone lymphoma cellsdecreased proliferation and increased apoptosisin vitro, and impaired lym-phoma developmentin vivo. These results show that cryptic deletions,insertions and/or point mutations inactivating genes within 7q32 are notcommon in SMZL, and suggest that IRF5 may be a haploinsufficienttumour suppressor in this lymphoma entity.