Integrative Analysis Reveals an Outcome-Associated and Targetable Pattern of p53 and Cell Cycle Deregulation in Diffuse Large B Cell Lymphoma

Stefano Monti, Bjoern Chapuy, Kunihiko Takeyama, Scott J. Rodig, Yansheng Hao, Kelly T. Yeda, Haig Inguilizian, Craig Mermel, Treeve Currie, Ahmet Dogan, Jeffery L. Kutok, Rameen Beroukhim, Donna Neuberg, Thomas M. Habermann, Gad Getz, Andrew L. Kung, Todd R. Golub, Margaret A. Shipp

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

Diffuse large B cell lymphoma (DLBCL) is a clinically and biologically heterogeneous disease with a high proliferation rate. By integrating copy number data with transcriptional profiles and performing pathway analysis in primary DLBCLs, we identified a comprehensive set of copy number alterations (CNAs) that decreased p53 activity and perturbed cell cycle regulation. Primary tumors either had multiple complementary alterations of p53 and cell cycle components or largely lacked these lesions. DLBCLs with p53 and cell cycle pathway CNAs had decreased abundance of p53 target transcripts and increased expression of E2F target genes and the Ki67 proliferation marker. CNAs of the CDKN2A-TP53-RB-E2F axis provide a structural basis for increased proliferation in DLBCL, predict outcome with current therapy, and suggest targeted treatment approaches.

Original languageEnglish (US)
Pages (from-to)359-372
Number of pages14
JournalCancer cell
Volume22
Issue number3
DOIs
StatePublished - Sep 11 2012

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Monti, S., Chapuy, B., Takeyama, K., Rodig, S. J., Hao, Y., Yeda, K. T., Inguilizian, H., Mermel, C., Currie, T., Dogan, A., Kutok, J. L., Beroukhim, R., Neuberg, D., Habermann, T. M., Getz, G., Kung, A. L., Golub, T. R., & Shipp, M. A. (2012). Integrative Analysis Reveals an Outcome-Associated and Targetable Pattern of p53 and Cell Cycle Deregulation in Diffuse Large B Cell Lymphoma. Cancer cell, 22(3), 359-372. https://doi.org/10.1016/j.ccr.2012.07.014