1. High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma.
- Author
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Fresquet V, Robles EF, Parker A, Martinez-Useros J, Mena M, Malumbres R, Agirre X, Catarino S, Arteta D, Osaba L, Mollejo M, Hernandez-Rivas JM, Calasanz MJ, Daibata M, Dyer MJ, Prosper F, Vizcarra E, Piris MÁ, Oscier D, and Martinez-Climent JA
- Subjects
- 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, Genetic, 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
- 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., (© 2012 Blackwell Publishing Ltd.)
- Published
- 2012
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