Genetic basis of PD-L1 overexpression in diffuse large B-cell lymphomas

Blood. 2016 Jun 16;127(24):3026-34. doi: 10.1182/blood-2015-12-686550. Epub 2016 Mar 30.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is one of the most common and aggressive types of B-cell lymphoma. Deregulation of proto-oncogene expression after a translocation, most notably to the immunoglobulin heavy-chain locus (IGH), is one of the hallmarks of DLBCL. Using whole-genome sequencing analysis, we have identified the PD-L1/PD-L2 locus as a recurrent translocation partner for IGH in DLBCL. PIM1 and TP63 were also identified as novel translocation partners for PD-L1/PD-L2 Fluorescence in situ hybridization was furthermore used to rapidly screen an expanded DLBCL cohort. Collectively, a subset of samples was found to be affected by gains (12%), amplifications (3%), and translocations (4%) of the PD-L1/PD-L2 locus. RNA sequencing data coupled with immunohistochemistry revealed that these cytogenetic alterations correlated with increased expression of PD-L1 but not of PD-L2 Moreover, cytogenetic alterations affecting the PD-L1/PD-L2 locus were more frequently observed in the non-germinal center B cell-like (non-GCB) subtype of DLBCL. These findings demonstrate the genetic basis of PD-L1 overexpression in DLBCL and suggest that treatments targeting the PD-1-PD-L1/PD-L2 axis might benefit DLBCL patients, especially those belonging to the more aggressive non-GCB subtype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / metabolism
  • B7-H1 Antigen / genetics*
  • Cohort Studies
  • Cytogenetic Analysis
  • DNA Copy Number Variations
  • Gene Amplification
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Genes, Immunoglobulin Heavy Chain
  • Genome-Wide Association Study
  • Germinal Center / metabolism
  • Germinal Center / pathology
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Translocation, Genetic
  • Up-Regulation / genetics

Substances

  • B7-H1 Antigen
  • CD274 protein, human