Genetic Landscapes of Relapsed and Refractory Diffuse Large B-Cell Lymphomas

Clin Cancer Res. 2016 May 1;22(9):2290-300. doi: 10.1158/1078-0432.CCR-15-2123. Epub 2015 Dec 8.


Purpose: Relapsed or refractory diffuse large B-cell lymphoma (rrDLBCL) is fatal in 90% of patients, and yet little is known about its biology.

Experimental design: Using exome sequencing, we characterized the mutation profiles of 38 rrDLBCL biopsies obtained at the time of progression after immunochemotherapy. To identify genes that may be associated with relapse, we compared the mutation frequency in samples obtained at relapse to an unrelated cohort of 138 diagnostic DLBCLs and separately amplified specific mutations in their matched diagnostic samples to identify clonal expansions.

Results: On the basis of a higher frequency at relapse and evidence for clonal selection, TP53, FOXO1, MLL3 (KMT2C), CCND3, NFKBIZ, and STAT6 emerged as top candidate genes implicated in therapeutic resistance. We observed individual examples of clonal expansions affecting genes whose mutations had not been previously associated with DLBCL including two regulators of NF-κB: NFKBIE and NFKBIZ We detected mutations that may be affect sensitivity to novel therapeutics, such as MYD88 and CD79B mutations, in 31% and 23% of patients with activated B-cell-type of rrDLBCL, respectively. We also identified recurrent STAT6 mutations affecting D419 in 36% of patients with the germinal center B (GCB) cell rrDLBCL. These were associated with activated JAK/STAT signaling, increased phospho-STAT6 protein expression and increased expression of STAT6 target genes.

Conclusions: This work improves our understanding of therapeutic resistance in rrDLBCL and has identified novel therapeutic opportunities especially for the high-risk patients with GCB-type rrDLBCL. Clin Cancer Res; 22(9); 2290-300. ©2015 AACR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • B-Lymphocytes / metabolism
  • CD79 Antigens / genetics
  • Cyclin D3 / genetics
  • Female
  • Forkhead Box Protein O1 / genetics
  • Gene Expression Regulation, Neoplastic / genetics
  • Germinal Center / metabolism
  • Humans
  • Janus Kinases / genetics
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Male
  • Middle Aged
  • Mutation / genetics
  • Myeloid Differentiation Factor 88 / genetics
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • NF-kappa B / genetics
  • Neoplasm Recurrence, Local / genetics*
  • Nuclear Proteins / genetics
  • Prospective Studies
  • STAT6 Transcription Factor / genetics
  • Signal Transduction / genetics
  • Tumor Suppressor Protein p53 / genetics


  • CD79 Antigens
  • Cyclin D3
  • Forkhead Box Protein O1
  • Myeloid Differentiation Factor 88
  • NF-kappa B
  • Nuclear Proteins
  • STAT6 Transcription Factor
  • Tumor Suppressor Protein p53
  • Myeloid-Lymphoid Leukemia Protein
  • Janus Kinases