Article
Nature 403, 503-511 (3 February 2000) | doi:10.1038/35000501; Received 11 November 1999; Accepted 10 January 2000
Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling
Ash A. Alizadeh1,2, Michael B. Eisen2,3,4, R. Eric Davis5, Chi Ma5, Izidore S. Lossos6, Andreas Rosenwald5, Jennifer C. Boldrick1, Hajeer Sabet5, Truc Tran5, Xin Yu5, John I. Powell7, Liming Yang7, Gerald E. Marti8, Troy Moore9, James Hudson, Jr9, Lisheng Lu10, David B. Lewis10, Robert Tibshirani11, Gavin Sherlock4, Wing C. Chan12, Timothy C. Greiner12, Dennis D. Weisenburger12, James O. Armitage13, Roger Warnke14, Ronald Levy6, Wyndham Wilson15, Michael R. Grever16, John C. Byrd17, David Botstein4, Patrick O. Brown1,18 and Louis M. Staudt5
- Departments of Biochemistry,
- Genetics,
- Pathology,
- Medicine,
- Pediatrics and
- Health Research & Policy and Statistics, and
- Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA
- Metabolism Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
- Bioinformatics and Molecular Analysis Section, CBEL, CIT, NIH, Bethesda, Maryland 20892, USA
- CBER, FDA, Bethesda, Maryland 20892, USA
- Research Genetics, Huntsville , Alabama 35801, USA
- Departments of Pathology and Microbiology, and
- Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
- Medicine Branch, Division of Clinical Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
- Johns Hopkins Oncology Center, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA
- Walter Reed Army Medical Center , Washington, DC 20307, USA
- These authors contributed equally to this work
- Present address: Life Sciences Division, Lawrence Orlando Berkeley National Labs and Department of Molecular and Cellular Biology, University of California, Berkeley , California 94720, USA.
Correspondence to: Louis M. Staudt5 Correspondence and requests for materials should be addressed to L.M.S. (Email: lstaudt@box-l.nih.gov) or P.O.B. (Email: pbrown@cmgm.stanford.edu ).
Abstract
Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin's lymphoma, is clinically heterogeneous: 40% of patients respond well to current therapy and have prolonged survival, whereas the remainder succumb to the disease. We proposed that this variability in natural history reflects unrecognized molecular heterogeneity in the tumours. Using DNA microarrays, we have conducted a systematic characterization of gene expression in B-cell malignancies. Here we show that there is diversity in gene expression among the tumours of DLBCL patients, apparently reflecting the variation in tumour proliferation rate, host response and differentiation state of the tumour. We identified two molecularly distinct forms of DLBCL which had gene expression patterns indicative of different stages of B-cell differentiation. One type expressed genes characteristic of germinal centre B cells ('germinal centre B-like DLBCL'); the second type expressed genes normally induced during in vitro activation of peripheral blood B cells ('activated B-like DLBCL'). Patients with germinal centre B-like DLBCL had a significantly better overall survival than those with activated B-like DLBCL. The molecular classification of tumours on the basis of gene expression can thus identify previously undetected and clinically significant subtypes of cancer.