High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma |
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Authors: | Vicente Fresquet Eloy F Robles Anton Parker Javier Martinez-Useros Maria Mena Raquel Malumbres Xabier Agirre Susana Catarino David Arteta Lourdes Osaba Manuela Mollejo Jesus M Hernandez-Rivas Maria Jose Calasanz Masanori Daibata Martin J S Dyer Felipe Prosper Esperanza Vizcarra Miguel-Ángel Piris David Oscier Jose Angel Martinez-Climent |
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Affiliation: | Division of Oncology, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain. |
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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. |
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Keywords: | B cell lymphoma IRF5 chromosome deletion |
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