Journal
BRITISH JOURNAL OF HAEMATOLOGY
Volume 158, Issue 6, Pages 712-726Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1365-2141.2012.09226.x
Keywords
B cell lymphoma; IRF5; chromosome deletion
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Funding
- Spanish Ministry of Science, Innovation and Health [PI081878, PS09/02437, RTICC-ISCIII-RD06/0020/0088-0080-0111-0078]
- UTE-CIMA project
- Spanish Ministry of Health
- Spanish Ministry of Science and Innovation
- Spanish Association Against Cancer (AECC) fellowship
- Grants-in-Aid for Scientific Research [23591391] Funding Source: KAKEN
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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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