title: High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma.
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.
authors: Division of Oncology, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain. vfresquet@unav.es
authors: Vicente
authors: V
authors: Fresquet
authors: Eloy F
authors: EF
authors: Robles
authors: Anton
authors: A
authors: Parker
authors: Javier
authors: J
authors: Martinez-Useros
authors: Maria
authors: M
authors: Mena
authors: Raquel
authors: R
authors: Malumbres
authors: Xabier
authors: X
authors: Agirre
authors: Susana
authors: S
authors: Catarino
authors: David
authors: D
authors: Arteta
authors: Lourdes
authors: L
authors: Osaba
authors: Manuela
authors: M
authors: Mollejo
authors: Jesus M
authors: JM
authors: Hernandez-Rivas
authors: Maria Jose
authors: MJ
authors: Calasanz
authors: Masanori
authors: M
authors: Daibata
authors: Martin J S
authors: MJ
authors: Dyer
authors: Felipe
authors: F
authors: Prosper
authors: Esperanza
authors: E
authors: Vizcarra
authors: Miguel-Ángel
authors: MÁ
authors: Piris
authors: David
authors: D
authors: Oscier
authors: Jose Angel
authors: JA
authors: Martinez-Climent
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000637:transplantation; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics* / Q000648:ultrastructure; D055028:Comparative Genomic Hybridization; D015972:Gene Expression Regulation, Neoplastic; D005803:Genes, Immunoglobulin; D016147:Genes, Tumor Suppressor; D056726:Genetic Association Studies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D050835:Interferon Regulatory Factors / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D053208:Kaplan-Meier Estimate; D018442:Lymphoma, B-Cell, Marginal Zone / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D017354:Point Mutation; D060888:Real-Time Polymerase Chain Reaction; D017384:Sequence Deletion; D013160:Splenic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D014178:Translocation, Genetic
chemical_list: C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D009363:Neoplasm Proteins