Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas

• Published in: Blood 2007-01, Vol.109 (1), p.271-280
• Main Authors: Mestre-Escorihuela, Cinta, Rubio-Moscardo, Fanny, Richter, Jose A., Siebert, Reiner, Climent, Joan, Fresquet, Vicente, Beltran, Elena, Agirre, Xabier, Marugan, Isabel, Marín, Miguel, Rosenwald, Andreas, Sugimoto, Kei-ji, Wheat, Luise M., Karran, E. Loraine, García, Juan F., Sanchez, Lydia, Prosper, Felipe, Staudt, Louis M., Pinkel, Daniel, Dyer, Martin J.S., Martinez-Climent, Jose A.
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing; Apoptosis - genetics; Apoptosis Regulatory Proteins - genetics; Bcl-2-Like Protein 11; Biopsy; Carrier Proteins - genetics; Cell Line, Tumor; Chromosome Mapping; Chromosomes, Human - genetics; Chromosomes, Human - ultrastructure; Cyclin-Dependent Kinase Inhibitor p18 - genetics; DNA Methylation; DNA Mutational Analysis; DNA, Neoplasm - genetics; Epigenesis, Genetic; Gene Dosage; Gene Expression Regulation, Neoplastic; Gene Silencing; Genes, Tumor Suppressor; Homeodomain Proteins - genetics; Homozygote; Humans; Lymphoma, B-Cell - classification; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - immunology; Lymphoma, B-Cell - pathology; Membrane Proteins - genetics; Nuclear Proteins - genetics; Nucleic Acid Hybridization; Oligonucleotide Array Sequence Analysis; Point Mutation; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-bcl-2 - genetics; RNA-Binding Proteins; Sequence Deletion; Sorting Nexins; Transcription Factors - genetics; Vesicular Transport Proteins - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-06-026500

Integrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Notably, the pattern of genetic and epigenetic inactivation differed among B-NHL subtypes. Thus, the P53-inducible PIG7/LITAF was silenced by homozygous deletion in primary mediastinal B-cell lymphoma and by promoter hypermethylation in germinal center lymphoma, the proapoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the proapoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma, and INK4c/P18 was silenced by biallelic mutation in mantle-cell lymphoma. Our microarray strategy has identified novel candidate tumor suppressor genes inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes.