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

doi:10.1016/j.ccr.2012.07.014

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

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132 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 language	English (US)
Pages (from-to)	359-372
Number of pages	14
Journal	Cancer cell
Volume	22
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2012.07.014
State	Published - Sep 11 2012

ASJC Scopus subject areas

Oncology
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

Monti, S, Chapuy, B, Takeyama, K, Rodig, SJ, Hao, Y, Yeda, KT, Inguilizian, H, Mermel, C, Currie, T, Dogan, A, Kutok, JL, Beroukhim, R, Neuberg, D, Habermann, TM, Getz, G, Kung, AL, Golub, TR & Shipp, MA 2012, 'Integrative Analysis Reveals an Outcome-Associated and Targetable Pattern of p53 and Cell Cycle Deregulation in Diffuse Large B Cell Lymphoma', Cancer cell, vol. 22, no. 3, pp. 359-372. https://doi.org/10.1016/j.ccr.2012.07.014

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

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.",

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

note = "Funding Information: This work was supported by NIH PO1CA092625. B.C. was supported by a grant from the German Research Foundation (DFG Ch 735/1-1). ",

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doi = "10.1016/j.ccr.2012.07.014",

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T1 - Integrative Analysis Reveals an Outcome-Associated and Targetable Pattern of p53 and Cell Cycle Deregulation in Diffuse Large B Cell Lymphoma

AU - Monti, Stefano

AU - Chapuy, Bjoern

AU - Takeyama, Kunihiko

AU - Rodig, Scott J.

AU - Hao, Yansheng

AU - Yeda, Kelly T.

AU - Inguilizian, Haig

AU - Mermel, Craig

AU - Currie, Treeve

AU - Dogan, Ahmet

AU - Kutok, Jeffery L.

AU - Beroukhim, Rameen

AU - Neuberg, Donna

AU - Habermann, Thomas M.

AU - Getz, Gad

AU - Kung, Andrew L.

AU - Golub, Todd R.

AU - Shipp, Margaret A.

N1 - Funding Information: This work was supported by NIH PO1CA092625. B.C. was supported by a grant from the German Research Foundation (DFG Ch 735/1-1).

PY - 2012/9/11

Y1 - 2012/9/11

N2 - 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.

AB - 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.

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

Abstract

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