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

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.

[1]  T. Hodgkin Excerpts from: On some morbid appearances of the absorbent glands and spleen , 1973 .

[2]  S. Flexner,et al.  On the Pathological Changes in Hodgkinʼs Disease, with Special Reference to its Relation to Tuberculosis , 1903 .

[3]  D. M. Weir,et al.  Handbook of experimental immunology , 1967 .

[4]  T. Grogan,et al.  Independent prognostic significance of a nuclear proliferation antigen in diffuse large cell lymphomas as determined by the monoclonal antibody Ki-67 , 1988 .

[5]  T. Grogan,et al.  Independent prognostic significance of a nuclear proliferation antigen in diffuse large cell lymphomas as determined by the monoclonal antibody Ki-67. , 1988, Blood.

[6]  S. Jalkanen,et al.  Lymphocyte homing and clinical behavior of non-Hodgkin's lymphoma. , 1991, The Journal of clinical investigation.

[7]  D. Bahler,et al.  Clonal evolution of a follicular lymphoma: evidence for antigen selection. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Emili Montserrat,et al.  A predictive model for aggressive non-Hodgkin's lymphoma. , 1993, The New England journal of medicine.

[9]  T M Grogan,et al.  Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. , 1993, The New England journal of medicine.

[10]  S. Leeder,et al.  A population based study , 1993, The Medical journal of Australia.

[11]  S. Bernasconi,et al.  The A-myb gene is preferentially expressed in tonsillar CD38+, CD39-, and sIgM- B lymphocytes and in Burkitt's lymphoma cell lines. , 1994, Journal of immunology.

[12]  Sa Rosenberg,et al.  Classification of lymphoid neoplasms [editorial; comment] [see comments] , 1994 .

[13]  Elaine S. Jaffe,et al.  A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. , 1994, Blood.

[14]  H Stein,et al.  A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. , 1994, Blood.

[15]  Ronald W. Davis,et al.  Quantitative Monitoring of Gene Expression Patterns with a Complementary DNA Microarray , 1995, Science.

[16]  S. Pileri,et al.  A specific monoclonal antibody (PG-B6) detects expression of the BCL-6 protein in germinal center B cells. , 1995, The American journal of pathology.

[17]  T. Taniguchi,et al.  Molecular cloning of LSIRF, a lymphoid-specific member of the interferon regulatory factor family that binds the interferon-stimulated response element (ISRE). , 1995, Nucleic acids research.

[18]  L. Penland,et al.  Use of a cDNA microarray to analyse gene expression patterns in human cancer , 1996, Nature Genetics.

[19]  M. Dyer,et al.  Molecular cloning of complex chromosomal translocation t(8;14;12)(q24.1;q32.3;q24.1) in a Burkitt lymphoma cell line defines a new gene (BCL7A) with homology to caldesmon. , 1996, Blood.

[20]  L. Staudt,et al.  BCL-6 expression during B-cell activation. , 1996, Blood.

[21]  J Hermans,et al.  Clinical significance of bcl2 and p53 protein expression in diffuse large B-cell lymphoma: a population-based study. , 1996, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  S. Pittaluga,et al.  BCL‐6 EXPRESSION IN REACTIVE LYMPHOID TISSUE AND IN B‐CELL NON‐HODGKIN'S LYMPHOMAS , 1996, The Journal of pathology.

[23]  J C Reed,et al.  Prognostic significance of Bcl-2 protein expression and Bcl-2 gene rearrangement in diffuse aggressive non-Hodgkin's lymphoma. , 1997, Blood.

[24]  R. Kurzrock,et al.  Prognostic Value of Serum Interleukin-6 in Diffuse Large-cell Lymphoma , 1997, Annals of Internal Medicine.

[25]  B. Nathwani,et al.  A clinical evaluation of the International Lymphoma Study Group Classification of non-Hodgkin's lymphoma: a report of the Non-Hodgkin's Lymphoma Classification Project , 1997 .

[26]  M. Hatano,et al.  Disruption of the Bcl6 Gene Results in an Impaired Germinal Center Formation , 1997, The Journal of experimental medicine.

[27]  B. Klein,et al.  Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma , 1997, Nature Genetics.

[28]  P. Pandolfi,et al.  The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation , 1997, Nature Genetics.

[29]  L. Staudt,et al.  Control of inflammation, cytokine expression, and germinal center formation by BCL-6. , 1997, Science.

[30]  T. Mak,et al.  Requirement for the Transcription Factor LSIRF/IRF4 for Mature B and T Lymphocyte Function , 1997, Science.

[31]  J. Sklar,et al.  Augmented Expression of a Human Gene for 8-oxoguanine DNA Glycosylase (MutM) in B Lymphocytes of the Dark Zone in Lymph Node Germinal Centers , 1997, The Journal of experimental medicine.

[32]  S. Tangye,et al.  Identification of Functional Human Splenic Memory B Cells by Expression of CD148 and CD27 , 1998, The Journal of experimental medicine.

[33]  J. Tschopp,et al.  Inhibition of fas death signals by FLIPs. , 1998, Current opinion in immunology.

[34]  Klaus Rajewsky,et al.  Somatic hypermutation in normal and transformed human B cells , 1998, Immunological reviews.

[35]  J Hermans,et al.  Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma. , 1998, Blood.

[36]  T. Rabbitts,et al.  LMO T-cell translocation oncogenes typify genes activated by chromosomal translocations that alter transcription and developmental processes. , 1998, Genes & development.

[37]  J. Vose,et al.  Current approaches to the management of non-Hodgkin's lymphoma. , 1998, Seminars in oncology.

[38]  K. Rajewsky,et al.  Human Immunoglobulin (Ig)M+IgD+ Peripheral Blood B Cells Expressing the CD27 Cell Surface Antigen Carry Somatically Mutated Variable Region Genes: CD27 as a General Marker for Somatically Mutated (Memory) B Cells , 1998, The Journal of experimental medicine.

[39]  M. Bittner,et al.  Gene expression profiling of alveolar rhabdomyosarcoma with cDNA microarrays. , 1998, Cancer research.

[40]  P. Biberfeld,et al.  The Inhibitor of Death Receptor Signaling, Flice-Inhibitory Protein Defines a New Class of Tumor Progression Factors , 1999, The Journal of experimental medicine.

[41]  J. Mesirov,et al.  Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. , 1999, Science.

[42]  R. Offringa,et al.  Immune Escape of Tumors in Vivo by Expression of Cellular Flice-Inhibitory Protein , 1999, The Journal of experimental medicine.

[43]  U. Alon,et al.  Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[44]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[45]  L. Hood,et al.  Monitoring gene expression profile changes in ovarian carcinomas using cDNA microarray. , 1999, Gene.

[46]  Christian A. Rees,et al.  Distinctive gene expression patterns in human mammary epithelial cells and breast cancers. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[47]  E Mahlamäki,et al.  Hormone therapy failure in human prostate cancer: analysis by complementary DNA and tissue microarrays. , 1999, Journal of the National Cancer Institute.

[48]  P. Brown,et al.  DNA arrays for analysis of gene expression. , 1999, Methods in enzymology.

[49]  M. Seto,et al.  Molecular and immunological dissection of diffuse large B cell lymphoma: CD5+, and CD5− with CD10+ groups may constitute clinically relevant subtypes , 1999, Leukemia.

[50]  Ash A. Alizadeh,et al.  The lymphochip: a specialized cDNA microarray for the genomic-scale analysis of gene expression in normal and malignant lymphocytes. , 1999, Cold Spring Harbor symposia on quantitative biology.

[51]  L. Staudt,et al.  Regulation of lymphocyte cell fate decisions and lymphomagenesis by BCL-6. , 1999, International reviews of immunology.

[52]  原田 信助 Molecular and immunological dissection of diffuse large B cell lymphoma : CD5[+], and CD5[-] with CD10[+] groups may constitute clinically relevant subtypes , 2000 .