Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment.

Several gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the "germinal center B cell-like" subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of "cell-of-origin" classification, "stromal signatures," IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL.

[1]  J. Burchenal,et al.  Treatment of acute lymphoblastic leukemia. , 1972, Annual review of medicine.

[2]  K. Pollok,et al.  Inducible T cell antigen 4-1BB. Analysis of expression and function. , 1993, Journal of immunology.

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

[4]  Lieping Chen,et al.  Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors , 1997, Nature Medicine.

[5]  A. Aruffo,et al.  4-1BB Costimulatory Signals Preferentially Induce CD8+ T Cell Proliferation and Lead to the Amplification In Vivo of Cytotoxic T Cell Responses , 1997, The Journal of experimental medicine.

[6]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[7]  Todd,et al.  Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning , 2002, Nature Medicine.

[8]  L. Staudt,et al.  The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.

[9]  B. E. C. Oiffier,et al.  CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma , 2002 .

[10]  Optimization of quantitative real-time RT-PCR parameters for the study of lymphoid malignancies , 2003, Leukemia.

[11]  A. Ferrando,et al.  Gene expression profiling in T-cell acute lymphoblastic leukemia. , 2003, Seminars in hematology.

[12]  Adrian Wiestner,et al.  A gene expression-based method to diagnose clinically distinct subgroups of diffuse large B cell lymphoma , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[13]  I. Lossos,et al.  Optimization of quantitative real-time RT-PCR parameters for the study of lymphoid malignancies , 2003, Leukemia.

[14]  L. Staudt,et al.  Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. , 2004, The New England journal of medicine.

[15]  T. Rabbitts,et al.  Activation of the T-cell oncogene LMO2 after gene therapy for X-linked severe combined immunodeficiency. , 2004, The New England journal of medicine.

[16]  L. Staudt,et al.  Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. , 2004, Blood.

[17]  L. Staudt,et al.  Loss of MHC class II gene and protein expression in diffuse large B-cell lymphoma is related to decreased tumor immunosurveillance and poor patient survival regardless of other prognostic factors: a follow-up study from the Leukemia and Lymphoma Molecular Profiling Project. , 2004, Blood.

[18]  Ash A. Alizadeh,et al.  Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. , 2004, The New England journal of medicine.

[19]  T. Golub,et al.  Molecular profiling of diffuse large B-cell lymphoma identifies robust subtypes including one characterized by host inflammatory response. , 2004, Blood.

[20]  P. Gaulard,et al.  Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  R. Spang,et al.  A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. , 2006, The New England journal of medicine.

[22]  I. Lossos,et al.  Prognostic biomarkers in diffuse large B-cell lymphoma. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  Jonathan M Irish,et al.  Altered B-cell receptor signaling kinetics distinguish human follicular lymphoma B cells from tumor-infiltrating nonmalignant B cells. , 2006, Blood.

[24]  Charles Lee,et al.  The cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia. , 2006, Blood.

[25]  A. López-Guillermo,et al.  CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. , 2006, The Lancet. Oncology.

[26]  C. Pui,et al.  Treatment of acute lymphoblastic leukemia. , 2006, New England Journal of Medicine.

[27]  R. Gascoyne,et al.  Clinical Trials and Observations , 2005 .

[28]  I. Lossos,et al.  The oncoprotein LMO2 is expressed in normal germinal-center B cells and in human B-cell lymphomas. , 2007, Blood.

[29]  Erratum: Optimization of RNA extraction from formalin-fixed, paraffin-embedded lymphoid tissues (Diagnostic Molecular Pathology (2007) 16, (61-72)) , 2007 .

[30]  L. Staudt,et al.  Stromal gene signatures in large-B-cell lymphomas. , 2008, The New England journal of medicine.

[31]  Benjamin Haibe-Kains,et al.  A comparative study of survival models for breast cancer prognostication based on microarray data: does a single gene beat them all? , 2008, Bioinform..

[32]  Comparing Standard IPI with Revised-IPI in Patients with Diffuse Large B-Cell Lymphoma: Which Has a More Differential Potential for Predicting the Outcomes after R-CHOP Chemotherapy. , 2008 .

[33]  Robert Tibshirani,et al.  LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[34]  I. Lossos.  Diffuse large B cell lymphoma: from gene expression profiling to prediction of outcome. , 2008, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[35]  R. Tibshirani,et al.  Paraffin-based 6-gene model predicts outcome in diffuse large B-cell lymphoma patients treated with R-CHOP. , 2007, Blood.

[36]  Kai Fu,et al.  A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy , 2009, Clinical Cancer Research.

[37]  M. Pfreundschuh,et al.  Hematology: Germinal center or nongerminal center DLBCL? , 2009, Nature Reviews Clinical Oncology.

[38]  Ash A. Alizadeh,et al.  Molecular outcome prediction in diffuse large-B-cell lymphoma. , 2009, The New England journal of medicine.

[39]  J. Borst,et al.  Mice deficient for CD137 ligand are predisposed to develop germinal center-derived B-cell lymphoma. , 2009, Blood.

[40]  Ash A. Alizadeh,et al.  Therapeutic effect of CD137 immunomodulation in lymphoma and its enhancement by Treg depletion. , 2009, Blood.

[41]  L. Staudt,et al.  Differential efficacy of bortezomib plus chemotherapy within molecular subtypes of diffuse large B-cell lymphoma. , 2009, Blood.

[42]  S. Koscielny.  Why Most Gene Expression Signatures of Tumors Have Not Been Useful in the Clinic , 2010, Science Translational Medicine.

[43]  J. Byrd,et al.  NCCN Clinical Practice Guidelines in Oncology: non-Hodgkin's lymphomas. , 2010, Journal of the National Comprehensive Cancer Network : JNCCN.

[44]  J. Byrd,et al.  Non-Hodgkin's lymphomas. , 2010, Journal of the National Comprehensive Cancer Network : JNCCN.

[45]  H. Varmus.  Ten years on--the human genome and medicine. , 2010, The New England journal of medicine.

[46]  Steven J. M. Jones,et al.  Tumor-associated macrophages and survival in classic Hodgkin's lymphoma. , 2010, The New England journal of medicine.

[47]  C. D. de Graaf,et al.  The Lmo2 Oncogene Initiates Leukemia in Mice by Inducing Thymocyte Self-Renewal , 2010, Science.

[48]  Dirk Hasenclever,et al.  Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  Ash A. Alizadeh,et al.  CD137 stimulation enhances the antilymphoma activity of anti-CD20 antibodies. , 2011, Blood.