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Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling

Naturevolume 403, pages503–511 (2000)Cite this article

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 duringin 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.

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Figure 1: Hierarchical clustering of gene expression data.
Figure 2: Expanded view of biologically distinct gene expression signatures defined by hierarchical clustering.
Figure 3: Discovery of DLBCL subtypes by gene expression profiling.
Figure 4: Relationship of DLBCL subgroups to normal B-lymphocyte differentiation and activation.
Figure 5: Clinically distinct DLBCL subgroups defined by gene expression profiling.

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Acknowledgements

We acknowledge the support of the Cancer Genome Anatomy Project (CGAP), led by B. Strausberg and R. Klausner. We also thank R. Klausner for comments on the manuscript; C. Prange for providing CGAP cDNA clones; H. Messner for providing DLBCL cell lines; H. Mostowski for sorting lymphocyte subpopulations by FACS; Holy Cross Hospital, Silver Spring, Maryland, for providing human tonsils; J. DeRisi for helpful advice on microarray technology; and members of the Staudt, Brown and Botstein laboratories for helpful discussions. Research at Stanford was supported by grants from the National Cancer Institute to D.B., R.L. and P.O.B. and by the Howard Hughes Medical Institute. P.O.B. is an Associate Investigator of the Howard Hughes Medical Institute. A.A. was initially supported by the Howard Hughes Medical Institute Research Scholar Program while at the NIH and then by the Medical Scientist Training Program at Stanford University. M.B.E. was supported by a Computational Molecular Biology Postdoctoral Fellowship from the Alfred E. Sloan Foundation.

Author information

Author notes

  1. Michael B. Eisen, Gavin Sherlock & David Botstein

    Present address: Life Sciences Division, Lawrence Orlando Berkeley National Labs and Department of Molecular and Cellular Biology, University of California, Berkeley, California, 94720, USA

  2. Ash A. Alizadeh, Michael B. Eisen and Patrick O. Brown: These authors contributed equally to this work

Authors and Affiliations

  1. Departments of Biochemistry,

    Ash A. Alizadeh, Jennifer C. Boldrick & Patrick O. Brown

  2. Genetics,

    Michael B. Eisen

  3. Pathology,

    Roger Warnke

  4. Medicine,

    Izidore S. Lossos & Ronald Levy

  5. Pediatrics,

    Lisheng Lu & David B. Lewis

  6. Health Research & Policy and Statistics,

    Robert Tibshirani

  7. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, 94305, California, USA

    Patrick O. Brown

  8. Division of Clinical Sciences, Metabolism Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    R. Eric Davis, Chi Ma, Andreas Rosenwald, Hajeer Sabet, Truc Tran, Xin Yu & Louis M. Staudt

  9. Bioinformatics and Molecular Analysis Section, CBEL, CIT, NIH, Bethesda, 20892, Maryland, USA

    John I. Powell & Liming Yang

  10. CBER, FDA, Bethesda, 20892, Maryland, USA

    Gerald E. Marti

  11. Research Genetics, Huntsville , 35801, Alabama, USA

    Troy Moore & James Hudson Jr

  12. Departments of Pathology and Microbiology,

    Wing C. Chan, Timothy C. Greiner & Dennis D. Weisenburger

  13. Internal Medicine, University of Nebraska Medical Center, Omaha, 68198, Nebraska, USA

    James O. Armitage

  14. Division of Clinical Sciences, Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Wyndham Wilson

  15. Johns Hopkins Oncology Center, Johns Hopkins School of Medicine, Baltimore, 21287, Maryland, USA

    Michael R. Grever

  16. Walter Reed Army Medical Center , Washington, DC, 20307, USA

    John C. Byrd

Authors
  1. Ash A. Alizadeh

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  2. Michael B. Eisen

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Correspondence toLouis M. Staudt.

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Alizadeh, A., Eisen, M., Davis, R.et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling.Nature403, 503–511 (2000). https://doi.org/10.1038/35000501

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