Are we ready to stratify treatment for diffuse large B-cell lymphoma using molecular hallmarks?

Sarah Barton, Eliza A. Hawkes, Andrew Wotherspoon, David Cunningham

Research output: Contribution to journalArticleResearchpeer-review

29 Citations (Scopus)

Abstract

The division of the heterogeneous entity of diffuse large Bcell lymphoma (DLBCL) into the ontogenic phenotypes of germinal center B-cell-like (GCB) and activated B-cell-like (ABC) is optimally determined by gene expression profiling (GEP), although simpler immunohistochemistry (IHC) algorithms are alternatively being used. The cell-of-origin (COO) classification assists in prognostication and may be predictive of response to therapy. Mounting data suggests that IHC methods of classifying COO may be inaccurate. GEP categorization of COO is superior in defining prognostically and biologically distinct DLBCL subtypes, but current barriers to its widescale use include inaccessibility, cost, and lack of methodological standardization and prospective validation. The poorer prognosis of ABC-DLBCL is frequently associated with constitutive activity in the NF-κB pathway and aberrations in upstream or downstream regulators of this pathway. The molecular mechanisms underlying lymphomagenesis in GCB-DLBCL are arguably less well defined, but C-REL amplification and mutations in BCL-2 and EZH2 are common. New technologies, such as nextgeneration sequencing, are rapidly revealing novel pathogenic genetic aberrations, and DLBCL treatment strategies are increasingly being designed focusing on distinctive pathogenic drivers within ontogenic phenotypes. This review examines emerging molecular targets and novel therapeutic agents in DLBCL, and discusses whether stratifying therapy for DLBCL using molecular features is merited by current preclinical and clinical evidence.

Original languageEnglish
Pages (from-to)1562-1573
Number of pages12
JournalThe Oncologist
Volume17
Issue number12
DOIs
Publication statusPublished - 2012
Externally publishedYes

Keywords

  • Diffuse
  • Drug therapy
  • Gene expression profiling
  • Immunohistochemistry
  • Large B-cell
  • Lymphoma
  • Molecular targeted therapy
  • Phenotype

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