Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes.

BACKGROUND Several gene-expression signatures can be used to predict the prognosis in diffuse large-B-cell lymphoma, but the lack of practical tests for a genome-scale analysis has restricted the use of this method. METHODS We studied 36 genes whose expression had been reported to predict survival in diffuse large-B-cell lymphoma. We measured the expression of each of these genes in independent samples of lymphoma from 66 patients by quantitative real-time polymerase-chain-reaction analyses and related the results to overall survival. RESULTS In a univariate analysis, genes were ranked on the basis of their ability to predict survival. The genes that were the strongest predictors were LMO2, BCL6, FN1, CCND2, SCYA3, and BCL2. We developed a multivariate model that was based on the expression of these six genes, and we validated the model in two independent microarray data sets. The model was independent of the International Prognostic Index and added to its predictive power. CONCLUSIONS Measurement of the expression of six genes is sufficient to predict overall survival in diffuse large-B-cell lymphoma.

[1]  D. Cox.  Regression Models and Life-Tables , 1972 .

[2]  C. Geary.  Leukemia , 1984, British Journal of Cancer.

[3]  W. Ludwig,et al.  TTG-2, a new gene encoding a cysteine-rich protein with the LIM motif, is overexpressed in acute T-cell leukaemia with the t(11;14)(p13;q11). , 1991, Oncogene.

[4]  M. Perutz,et al.  The rhombotin family of cysteine-rich LIM-domain oncogenes: distinct members are involved in T-cell translocations to human chromosomes 11p15 and 11p13. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[5]  H. Tilly,et al.  LAZ3, a novel zinc–finger encoding gene, is disrupted by recurring chromosome 3q27 translocations in human lymphomas , 1993, Nature Genetics.

[6]  M. Evans,et al.  The Oncogenic Cysteine-rich LIM domain protein Rbtn2 is essential for erythroid development , 1994, Cell.

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

[8]  F. Ajchenbaum‐Cymbalista,et al.  Overexpression of cyclin D2 in chronic B-cell malignancies. , 1995, Blood.

[9]  C. Sherr.  Mammalian G1 cyclins and cell cycle progression. , 1995, Proceedings of the Association of American Physicians.

[10]  K. Offit,et al.  BCL-6 protein is expressed in germinal-center B cells. , 1995, Blood.

[11]  D C Linch,et al.  Prognostic significance of BCL-2 expression and bcl-2 major breakpoint region rearrangement in diffuse large cell non-Hodgkin's lymphoma: a British National Lymphoma Investigation Study. , 1996, Blood.

[12]  P. Proost,et al.  The role of chemokines in inflammation , 1996, International journal of clinical & laboratory research.

[13]  J Diebold,et al.  Prognostic significance of bcl-2 protein expression in aggressive non-Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA). , 1996, Blood.

[14]  R S Chaganti,et al.  BCL-6, a POZ/zinc-finger protein, is a sequence-specific transcriptional repressor. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[15]  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.

[16]  L. Staudt,et al.  Transcriptional repression by the proto-oncogene BCL-6. , 1996, Oncogene.

[17]  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.

[18]  P. Koduru,et al.  Correlation between mutation in P53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin's lymphoma. , 1997, Blood.

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

[20]  H. Saito,et al.  Mutations of the p53 gene as a prognostic factor in aggressive B-cell lymphoma. , 1997, The New England journal of medicine.

[21]  L. Staudt,et al.  T helper type 2 inflammatory disease in the absence of interleukin 4 and transcription factor STAT6. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[24]  E. Jaffe,et al.  Transcription factor B-cell-specific activator protein (BSAP) is differentially expressed in B cells and in subsets of B-cell lymphomas. , 1998, Blood.

[25]  K. Ohshima,et al.  Prognostic clinicopathologic factors, including immunologic expression in diffuse large B‐cell lymphomas , 1999, Pathology international.

[26]  J Hermans,et al.  CD44 expression predicts disease outcome in localized large B cell lymphoma , 1999, Leukemia.

[27]  D. Louis,et al.  Frequent disruption of the RB1 pathway in diffuse large B cell lymphoma: prognostic significance of E2F-1 and p16INK4A , 2000, Leukemia.

[28]  Eric S. Lander,et al.  Genomic analysis of metastasis reveals an essential role for RhoC , 2000, Nature.

[29]  J Diebold,et al.  Prognostic significance of survivin expression in diffuse large B-cell lymphomas. , 2000, Blood.

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

[31]  L. Staudt,et al.  BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. , 2000, Immunity.

[32]  T. Rabbitts,et al.  The oncogenic LIM-only transcription factor Lmo2 regulates angiogenesis but not vasculogenesis in mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[33]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[34]  correction: Genomic analysis of metastasis reveals an essential role for RhoC , 2001, Nature.

[35]  D. Mosher.  A role for fibronectin in self-repair after ischemic injury , 2001, Nature Medicine.

[36]  R. W. Davis,et al.  Global analysis of ATM polymorphism reveals significant functional constraint. , 2001, American journal of human genetics.

[37]  R Tibshirani,et al.  Expression of a single gene, BCL-6, strongly predicts survival in patients with diffuse large B-cell lymphoma. , 2001, Blood.

[38]  Jiang Li,et al.  Differential gene expression patterns revealed by oligonucleotide versus long cDNA arrays. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[39]  Lucila Ohno-Machado,et al.  Analysis of matched mRNA measurements from two different microarray technologies , 2002, Bioinform..

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

[41]  S. Barrans,et al.  Germinal center phenotype and bcl-2 expression combined with the International Prognostic Index improves patient risk stratification in diffuse large B-cell lymphoma. , 2002, Blood.

[42]  S. Sealfon,et al.  Accuracy and calibration of commercial oligonucleotide and custom cDNA microarrays. , 2002, Nucleic acids research.

[43]  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.

[44]  Geoffrey J McLachlan,et al.  Selection bias in gene extraction on the basis of microarray gene-expression data , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Robert Tibshirani,et al.  HGAL is a novel interleukin-4-inducible gene that strongly predicts survival in diffuse large B-cell lymphoma. , 2003, Blood.

[46]  Emili Montserrat,et al.  Clinical impact of the differentiation profile assessed by immunophenotyping in patients with diffuse large B-cell lymphoma. , 2003, Blood.

[47]  M. Radmacher,et al.  Pitfalls in the use of DNA microarray data for diagnostic and prognostic classification. , 2003, Journal of the National Cancer Institute.

[48]  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.

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