title: Prediction of survival in diffuse large B-cell lymphoma based on the expression of 2 genes reflecting tumor and microenvironment.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Oncology, Stanford University, Stanford, CA, USA. arasha@stanford.edu
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Gentles
authors.forename: Alvaro J
authors.initials: AJ
authors.lastname: Alencar
authors.forename: Chih Long
authors.initials: CL
authors.lastname: Liu
authors.forename: Holbrook E
authors.initials: HE
authors.lastname: Kohrt
authors.forename: Roch
authors.initials: R
authors.lastname: Houot
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Goldstein
authors.forename: Shuchun
authors.initials: S
authors.lastname: Zhao
authors.forename: Yasodha
authors.initials: Y
authors.lastname: Natkunam
authors.forename: Ranjana H
authors.initials: RH
authors.lastname: Advani
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
authors.forename: Javier
authors.initials: J
authors.lastname: Briones
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Tibshirani
authors.forename: June H
authors.initials: JH
authors.lastname: Myklebust
authors.forename: Sylvia K
authors.initials: SK
authors.lastname: Plevritis
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.forename: Ronald
authors.initials: R
authors.lastname: Levy
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000502:physiology; D002648:Child; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D060588:LIM Domain Proteins; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D008667:Metalloproteins / Q000235:genetics / Q000502:physiology; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins; D016019:Survival Analysis; D059016:Tumor Microenvironment / Q000235:genetics* / Q000276:immunology; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000235:genetics / Q000502:physiology; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C085117:LMO2 protein, human; D008667:Metalloproteins; D011518:Proto-Oncogene Proteins; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9