High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma.
Br J Haematol, 2012/9;158(6):712-26.
Fresquet V[1], 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, Martinez-Climent JA
Affiliations
PMID: 22816737DOI: 10.1111/j.1365-2141.2012.09226.x
Impact factor: 8.615
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.
MeSH terms
Animals; Apoptosis; Cell Division; Cell Line, Tumor; Chromosomes, Human, Pair 7; Comparative Genomic Hybridization; Gene Expression Regulation, Neoplastic; Genes, Immunoglobulin; Genes, Tumor Suppressor; Genetic Association Studies; High-Throughput Nucleotide Sequencing; Humans; Interferon Regulatory Factors; Kaplan-Meier Estimate; Lymphoma, B-Cell, Marginal Zone; Mice; Mice, Knockout; Neoplasm Proteins; Oligonucleotide Array Sequence Analysis; Point Mutation; Real-Time Polymerase Chain Reaction; Sequence Deletion; Splenic Neoplasms; Translocation, Genetic
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