A three-gene signature based on MYC, BCL-2 and NFKBIA improves risk stratification in diffuse large B-cell lymphoma

E. Derenzini, S. Mazzara, F. Melle, G. Motta, M. Fabbri, R. Bruna, C. Agostinelli, A. Cesano, C.A. Corsini, N. Chen, S. Righi, E. Sabattini, A. Chiappella, A. Calleri, S. Fiori, V. Tabanelli, A. Cabras, G. Pruneri, U. Vitolo, A.M. GianniA. Rambaldi, P. Corradini, P.L. Zinzani, C. Tarella, S. Pileri

Research output: Contribution to journalArticlepeer-review

Abstract

Recent randomized trials focused on gene expression-based determination of the cell of origin in diffuse large B-cell lymphoma could not show significant improvements by adding novel agents to standard chemoimmunotherapy. The aim of this study was the identification of a gene signature able to refine current prognostication algorithms and applicable to clinical practice. Here we used a targeted gene expression profiling panel combining the Lymph2Cx signature for cell of origin classification with additional targets including MYC, BCL-2 and NFKBIA, in 186 patients from two randomized trials (discovery cohort) (clinicaltrials gov. Identifier: NCT00355199 and NCT00499018). Data were validated in three independent series (two large public datasets and a real-life cohort). By integrating the cell of origin, MYC/BCL-2 double expressor status and NFKBIA expression, we defined a three-gene signature combining MYC, BCL-2 and NFKBIA (MBN-signature), which outperformed the MYC/BCL-2 double expressor status in multivariate analysis, and allowed further risk stratification within the germinal center B-cell/unclassified subset. The high-risk (MBN Sig-high) subgroup identified the vast majority of double hit cases and a significant fraction of activated B-cell-derived diffuse large B-cell lymphomas. These results were validated in three independent series including a cohort from the REMoDL-B trial, where, in an exploratory ad hoc analysis, the addition of bortezomib in the MBN Sig-high subgroup provided a progression free survival advantage compared with standard chemoimmunotherapy. These data indicate that a simple three-gene signature based on MYC, BCL-2 and NFKBIA could refine the prognostic stratification in diffuse large B-cell lymphoma, and might be the basis for future precision-therapy approaches. ©2021 Ferrata Storti Foundation
Original languageEnglish
Pages (from-to)2405-2416
Number of pages12
JournalHaematologica
Volume106
Issue number9
DOIs
Publication statusPublished - 2021

Keywords

  • bortezomib
  • I kappa B kinase alpha
  • Myc protein
  • protein bcl 2
  • Article
  • cancer prognosis
  • controlled study
  • decision tree
  • diagnostic test accuracy study
  • diffuse large B cell lymphoma
  • fluorescence in situ hybridization
  • gene expression profiling
  • human
  • human tissue
  • immunohistochemistry
  • International Prognostic Index
  • major clinical study
  • overall survival
  • phase 3 clinical trial
  • progression free survival
  • prospective study
  • randomized controlled trial
  • receiver operating characteristic
  • risk assessment
  • univariate analysis

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