Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways

Georg Lenz, George W. Wright, N. C Tolga Emre, Holger Kohlhammer, Sandeep S. Dave, R. Eric Davis, Shannon Carty, Lloyd T. Lam, A. L. Shaffer, Wenming Xiao, John Powell, Andreas Rosenwald, German Ott, Hans Konrad Muller-Hermelink, Randy D. Gascoyne, Joseph M. Connors, Elias Campo, Elaine S. Jaffe, Jan Delabie, Erlend B. SmelandLisa Rimsza, Richard I. Fisher, Dennis D. Weisenburger, Wing C. Chan, Louis M. Staudt

Research output: Contribution to journalArticle

646 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)13520-13525
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number36
DOIs
StatePublished - Sep 9 2008
Externally publishedYes

Fingerprint

Lymphoma, Large B-Cell, Diffuse
B-Lymphocytes
Germinal Center
B-Cell Lymphoma
Trisomy
Gene Expression Profiling
Oncogenes
Chromosomes, Human, Pair 19
Cell Line
Poisons
RNA Interference
MicroRNAs
Chromosome Aberrations
Neoplasms
Transcription Factors
Genome

Keywords

  • Comparative genomic hybridization
  • Gene-expression profiling
  • Oncogenes
  • Tumor suppressor genes

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Lenz, G., Wright, G. W., Emre, N. C. T., Kohlhammer, H., Dave, S. S., Davis, R. E., ... Staudt, L. M. (2008). Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. Proceedings of the National Academy of Sciences of the United States of America, 105(36), 13520-13525. https://doi.org/10.1073/pnas.0804295105

Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. / Lenz, Georg; Wright, George W.; Emre, N. C Tolga; Kohlhammer, Holger; Dave, Sandeep S.; Davis, R. Eric; Carty, Shannon; Lam, Lloyd T.; Shaffer, A. L.; Xiao, Wenming; Powell, John; Rosenwald, Andreas; Ott, German; Muller-Hermelink, Hans Konrad; Gascoyne, Randy D.; Connors, Joseph M.; Campo, Elias; Jaffe, Elaine S.; Delabie, Jan; Smeland, Erlend B.; Rimsza, Lisa; Fisher, Richard I.; Weisenburger, Dennis D.; Chan, Wing C.; Staudt, Louis M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 36, 09.09.2008, p. 13520-13525.

Research output: Contribution to journalArticle

Lenz, G, Wright, GW, Emre, NCT, Kohlhammer, H, Dave, SS, Davis, RE, Carty, S, Lam, LT, Shaffer, AL, Xiao, W, Powell, J, Rosenwald, A, Ott, G, Muller-Hermelink, HK, Gascoyne, RD, Connors, JM, Campo, E, Jaffe, ES, Delabie, J, Smeland, EB, Rimsza, L, Fisher, RI, Weisenburger, DD, Chan, WC & Staudt, LM 2008, 'Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 36, pp. 13520-13525. https://doi.org/10.1073/pnas.0804295105
Lenz, Georg ; Wright, George W. ; Emre, N. C Tolga ; Kohlhammer, Holger ; Dave, Sandeep S. ; Davis, R. Eric ; Carty, Shannon ; Lam, Lloyd T. ; Shaffer, A. L. ; Xiao, Wenming ; Powell, John ; Rosenwald, Andreas ; Ott, German ; Muller-Hermelink, Hans Konrad ; Gascoyne, Randy D. ; Connors, Joseph M. ; Campo, Elias ; Jaffe, Elaine S. ; Delabie, Jan ; Smeland, Erlend B. ; Rimsza, Lisa ; Fisher, Richard I. ; Weisenburger, Dennis D. ; Chan, Wing C. ; Staudt, Louis M. / Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 36. pp. 13520-13525.
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AU - Davis, R. Eric

AU - Carty, Shannon

AU - Lam, Lloyd T.

AU - Shaffer, A. L.

AU - Xiao, Wenming

AU - Powell, John

AU - Rosenwald, Andreas

AU - Ott, German

AU - Muller-Hermelink, Hans Konrad

AU - Gascoyne, Randy D.

AU - Connors, Joseph M.

AU - Campo, Elias

AU - Jaffe, Elaine S.

AU - Delabie, Jan

AU - Smeland, Erlend B.

AU - Rimsza, Lisa

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