ABSTRACT
Using high-resolution genomic microarray analysis, a distinct genomic profile was defined in 114 samples from patients with splenic marginal zone lymphoma (SMZL). Deletion or uniparental disomy of chromosome 7q were detected in 42 of 114 (37%) SMZLs but in only nine of 170 (5%) mature B-cell lymphomas (P < 0·00001). The presence of unmutated IGHV, genomic complexity, 17p13-TP53 deletion and 8q-MYC gain, but not 7q deletion, correlated with shorter overall survival of SMZL patients. Mapping studies narrowed down a commonly deleted region of 2·7 Mb in 7q32.1-q32.2 spanning a region between the SND1 and COPG2 genes. High-throughput sequencing analysis of the 7q32-deleted segment did not identify biallelic deletions/insertions or clear pathogenic gene mutations, but detected six nucleotide changes in IRF5 (n = 2), TMEM209 (n = 2), CALU (n = 1) and ZC3HC1 (n = 1) not found in healthy individuals. Comparative expression analysis found a fourfold down-regulation of IRF5 gene in lymphomas with 7q32 deletion versus non-deleted tumours (P = 0·032). Ectopic expression of IRF5 in marginal-zone lymphoma cells decreased proliferation and increased apoptosis in vitro, and impaired lymphoma development in vivo. These results show that cryptic deletions, insertions and/or point mutations inactivating genes within 7q32 are not common in SMZL, and suggest that IRF5 may be a haploinsufficient tumour suppressor in this lymphoma entity.
Subject(s)
Chromosomes, Human, Pair 7/genetics , Genes, Tumor Suppressor , Genetic Association Studies , High-Throughput Nucleotide Sequencing , Interferon Regulatory Factors/genetics , Lymphoma, B-Cell, Marginal Zone/genetics , Neoplasm Proteins/genetics , Oligonucleotide Array Sequence Analysis/methods , Sequence Deletion , Splenic Neoplasms/genetics , Animals , Apoptosis/genetics , Cell Division/drug effects , Cell Line, Tumor/transplantation , Chromosomes, Human, Pair 7/ultrastructure , Comparative Genomic Hybridization , Gene Expression Regulation, Neoplastic , Genes, Immunoglobulin , Humans , Interferon Regulatory Factors/biosynthesis , Interferon Regulatory Factors/deficiency , Interferon Regulatory Factors/physiology , Kaplan-Meier Estimate , Lymphoma, B-Cell, Marginal Zone/mortality , Lymphoma, B-Cell, Marginal Zone/pathology , Mice , Mice, Knockout , Neoplasm Proteins/biosynthesis , Neoplasm Proteins/physiology , Point Mutation , Real-Time Polymerase Chain Reaction , Splenic Neoplasms/mortality , Splenic Neoplasms/pathology , Translocation, GeneticABSTRACT
Among 20 cases of typical splenic marginal zone lymphoma (SMZL), two cases had blastic transformation. The genetic mechanisms underlying the morphologic transformation were investigated by comparing genetic changes in initial and blastic phases. A complex karyotype including trisomy of 3q and genomic gain of 17q22-q24 was seen in both cases at diagnosis. However, the extra copy of 3q was lost during the transformation process in both tumors. Additionally, the Karpas 1718 cell line, which was derived from a patient with transformed SMZL and carried a trisomy of 3q, also evidenced the spontaneous loss of the extra 3q during the culturing process. Other acquired abnormalities observed exclusively in the transformation phase included amplification and/or translocation of bands 7p22-q22 and 19p13. These findings suggest that the loss of + 3q and the acquisition of other genomic imbalances may represent unique markers for the transformation process of SMZL. We hypothesize that the trisomy of 3q may correlate with the indolent nature of SMZL, and that the loss of this acquired abnormality leads to or accompanies the development of blastic tumors.
