The Journal of Experimental Medicine
StemCell Technologies
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Published 15 September 2003. doi:10.1084/jem.20031074
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© Rockefeller University Press, 0022-1007/2003/9/851 $5.00
The Journal of Experimental Medicine, Volume 198, Number 6, 851-862

Molecular Diagnosis of Primary Mediastinal B Cell Lymphoma Identifies a Clinically Favorable Subgroup of Diffuse Large B Cell Lymphoma Related to Hodgkin Lymphoma

Andreas Rosenwald1, George Wright5, Karen Leroy6, Xin Yu1, Philippe Gaulard6, Randy D. Gascoyne15, Wing C. Chan7, Tong Zhao7, Corinne Haioun6, Timothy C. Greiner7, Dennis D. Weisenburger7, James C. Lynch8, Julie Vose9, James O. Armitage9, Erlend B. Smeland10, Stein Kvaloy11, Harald Holte11, Jan Delabie12, Elias Campo13, Emili Montserrat13, Armando Lopez-Guillermo13, German Ott14, H. Konrad Muller-Hermelink14, Joseph M. Connors15, Rita Braziel16,17, Thomas M. Grogan16,18, Richard I. Fisher16,20, Thomas P. Miller16,19, Michael LeBlanc16,21, Michael Chiorazzi1, Hong Zhao1, Liming Yang22, John Powell22, Wyndham H. Wilson2, Elaine S. Jaffe3, Richard Simon5, Richard D. Klausner4 and Louis M. Staudt1

1 Metabolism Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
2 Medicine Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
3 Laboratory of Pathology, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
4 Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892
5 Biometric Research Branch, Division of Cancer Treatment and Diagnosis, NCI, NIH, Bethesda, MD 20892
6 Department of Pathology, Hôpital Henri Mondor, 94000 Créteil, France
7 Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198
8 Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE 68198
9 Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198
10 Department of Immunology, The Norwegian Radium Hospital, N-0310 Oslo, Norway
11 Department of Oncology, The Norwegian Radium Hospital, N-0310 Oslo, Norway
12 Department of Pathology, The Norwegian Radium Hospital, N-0310 Oslo, Norway
13 Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain
14 Department of Pathology, University of Würzburg, 97070 Würzburg, Germany
15 British Columbia Cancer Center, Vancouver, British Columbia, Canada V5Z 4E6
16 Southwest Oncology Group, Oregon Health and Science University, Portland, OR 97239
17 Department of Pathology, Oregon Health and Science University, Portland, OR 97239
18 Department of Pathology, University of Arizona Cancer Center, Tucson, AZ 85724
19 Department of Medicine, University of Arizona Cancer Center, Tucson, AZ 85724
20 James P. Wilmot Cancer Center, University of Rochester School of Medicine, Rochester, NY 14642
21 Fred Hutchinson Cancer Research Center, Seattle, WA 98109
22 Bioinformatics and Molecular Analysis Section, CBEL, CIT, NIH, Bethesda, MD 20892

Address correspondence to Louis M. Staudt, Metabolism Branch, CCR, NCI, Bldg. 10, Rm. 4N114, NIH, Bethesda, MD 20892. Phone: (301) 402-1892; Fax: (301) 496-9956; email: lstaudt{at}mail.nih.gov

Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas frequently involved other thoracic structures but not extrathoracic sites typical of other DLBCLs. PMBL patients had a relatively favorable clinical outcome, with a 5-yr survival rate of 64% compared with 46% for other DLBCL patients. Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkin lymphoma cells. PDL2, which encodes a regulator of T cell activation, was the gene that best discriminated PMBL from other DLBCLs and was also highly expressed in Hodgkin lymphoma cells. The genomic loci for PDL2 and several neighboring genes were amplified in over half of the PMBLs and in Hodgkin lymphoma cell lines. The molecular diagnosis of PMBL should significantly aid in the development of therapies tailored to this clinically and pathogenetically distinctive subgroup of DLBCL.

Key Words: gene expression profiling • microarray • outcome prediction • PMBL • DLBCL


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