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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3183-3190.
Prepublished online as a Blood First Edition Paper on July 26, 2005; DOI 10.1182/blood-2005-04-1399.
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NEOPLASIA
Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction
Silvia Bea,
Andreas Zettl,
George Wright,
Itziar Salaverria,
Philipp Jehn,
Victor Moreno,
Christof Burek,
German Ott,
Xavier Puig,
Liming Yang,
Armando Lopez-Guillermo,
Wing C. Chan,
Timothy C. Greiner,
Dennis D. Weisenburger,
James O. Armitage,
Randy D. Gascoyne,
Joseph M. Connors,
Thomas M. Grogan,
Rita Braziel,
Richard I. Fisher,
Erlend B. Smeland,
Stein Kvaloy,
Harald Holte,
Jan Delabie,
Richard Simon,
John Powell,
Wyndham H. Wilson,
Elaine S. Jaffe,
Emili Montserrat,
Hans-Konrad Muller-Hermelink,
Louis M. Staudt,
Elias Campo,
Andreas Rosenwald, for the Lymphoma/Leukemia Molecular Profiling Project
From the Department of Pathology and the Hematology Hospital Clinic, University of Barcelona, the Information and Studies Service, Catalan Department of Health, and the Cancer Epidemiology Service, IDIBELL Catalan Institute of Oncology and Laboratori d'Estadistica i Epidemiologia, Faculty of Medicine, Autonomous University of Barcelona, Spain; the Department of Pathology, University of Würzburg, Germany; Biometric Research, Medicine, Pathology, and Metabolism Branch, National Cancer Institute (NCI), and the Bioinformatics and Molecular Analysis Section, Computational Bioscience and Engineering Laboratory (CBEL), Center for Information Technology (CIT), National Institutes of Health (NIH), Bethesda, MD; the Department of Pathology and Microbiology and the Department of Internal Medicine, University of Nebraska Medical Center, Omaha; the Department of Pathology, British Columbia Cancer Center, Vancouver, BC, Canada; the Southwest Oncology Group, and the Department of Pathology, Oregon Health and Science University, Portland; the Department of Pathology and Medicine, University of Arizona Cancer Center, Tucson; the James P. Wilmot Cancer Center, University of Rochester School of Medicine, NY; and the Departments of Immunology, Oncology, and Pathology, The Norwegian Radium Hospital, Oslo, Norway.
Gene-expression profiling has identified 3 major subgroups of diffuse large B-cell lymphoma (DLBCL): germinal center B-cell-like (GCB), activated B-cell-like (ABC), and primary mediastinal DLBCL (PMBCL). Using comparative genomic hybridization (CGH), we investigated the genetic alterations of 224 cases of untreated DLBCL (87 GCB-DLBCL, 77 ABC-DLBCL, 19 PMBCL, and 41 unclassified DLBCL) previously characterized by gene-expression profiling. The DLBCL subgroups differed significantly in the frequency of particular chromosomal aberrations. ABC-DLBCL had frequent trisomy 3, gains of 3q and 18q21-q22, and losses of 6q21-q22, whereas GCB-DLBCL had frequent gains of 12q12, and PMBCL had gains of 9p21-pter and 2p14-p16. Parallel analysis of CGH alterations, locus-specific gene-expression profiles, and global gene-expression signatures revealed that DNA amplifications and gains had a substantial impact on the expression of genes in the involved chromosomal regions, and some genes were overexpressed in a DLBCL subgroup-specific fashion. Unexpectedly, specific chromosomal alterations were associated with significant changes in gene-expression signatures that reflect various aspects of lymphoma cell biology as well as the host response to the lymphoma. In addition, gains involving the chromosomal region 3p11-p12 provided prognostic information that was statistically independent of the previously defined gene-expression-based survival model, thereby improving its predictive power.
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