High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma

作者：Fresquet Vicente; Robles Eloy F; Parker Anton; Martinez Useros Javier; Mena Maria; Malumbres Raquel; Agirre Xabier; Catarino Susana; Arteta David; Osaba Lourdes; Mollejo Manuela; Hernandez Rivas Jesus M; Jose Ca****nz Maria; Daibata Masanori; Dyer Martin J S; Prosper Felipe; Vizcarra Esperanza; Piris Miguel Angel; Oscier David; Angel Martinez Climent Jose

来源：British Journal of Haematology, 2012, 158(6): 712-726.

DOI：10.1111/j.1365-2141.2012.09226.x

• B cell lymphoma
• IRF5
• chromosome deletion

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 %26lt; 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.

• 出版日期2012-9