Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways
| Autor: | Lisa M. Rimsza, Lloyd T. Lam, Elaine S. Jaffe, Elias Campo, Sandeep S. Dave, Arthur L. Shaffer, N. C. Tolga Emre, Dennis D. Weisenburger, German Ott, Hans Konrad Müller-Hermelink, Randy D. Gascoyne, John Powell, Wing C. Chan, Holger Kohlhammer, George E. Wright, Shannon A. Carty, Jan Delabie, Wenming Xiao, Joseph M. Connors, Georg Lenz, Erlend B. Smeland, Andreas Rosenwald, R. Eric Davis, Richard I. Fisher, Louis M. Staudt |
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| Rok vydání: | 2008 |
| Předmět: |
Cell Survival
Biopsy Copy number analysis Biology immune system diseases hemic and lymphatic diseases medicine Humans PTEN neoplasms Chromosome Aberrations Oncogene Proteins Multidisciplinary Genome Human Gene Expression Profiling Tumor Suppressor Proteins Germinal center FOXP1 Biological Sciences Amplicon Prognosis medicine.disease Molecular biology Gene Expression Regulation Neoplastic Chromosome 3 biology.protein Cancer research Lymphoma Large B-Cell Diffuse Diffuse large B-cell lymphoma Comparative genomic hybridization |
| Zdroj: | Proceedings of the National Academy of Sciences. 105:13520-13525 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.0804295105 |
| Popis: | Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes ( P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB , which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a / ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17–92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways. |
| Databáze: | OpenAIRE |
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