Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma

Blood. 2012 Oct 25;120(17):3530-40. doi: 10.1182/blood-2012-06-439570. Epub 2012 Sep 5.

Abstract

In classical Hodgkin lymphoma (CHL), 20%-30% of patients experience relapse or progressive disease after initial treatment. The pathogenesis and biology of treatment failure are still poorly understood, in part because the molecular phenotype of the rare malignant Hodgkin Reed-Sternberg (HRS) cells is difficult to study. Here we examined microdissected HRS cells from 29 CHL patients and 5 CHL-derived cell lines by gene expression profiling. We found significant overlap of HL-specific gene expression in primary HRS cells and HL cell lines, but also differences, including surface receptor signaling pathways. Using integrative analysis tools, we identified target genes with expression levels that significantly correlated with genomic copy-number changes in primary HRS cells. Furthermore, we found a macrophage-like signature in HRS cells that significantly correlated with treatment failure. CSF1R is a representative of this signature, and its expression was significantly associated with progression-free and overall survival in an independent set of 132 patients assessed by mRNA in situ hybridization. A combined score of CSF1R in situ hybridization and CD68 immunohistochemistry was an independent predictor for progression-free survival in multivariate analysis. In summary, our data reveal novel insights into the pathobiology of treatment failure and suggest CSF1R as a drug target of at-risk CHL.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antigens, CD / genetics*
  • Antigens, Differentiation, Myelomonocytic / genetics*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / genetics*
  • Cell Line, Tumor
  • Female
  • Gene Dosage
  • Gene Expression / drug effects
  • Gene Expression Profiling
  • Hodgkin Disease / drug therapy
  • Hodgkin Disease / genetics*
  • Hodgkin Disease / mortality
  • Hodgkin Disease / pathology
  • Humans
  • In Situ Hybridization
  • Laser Capture Microdissection
  • Male
  • Middle Aged
  • Predictive Value of Tests
  • RNA, Messenger / biosynthesis
  • Receptor, Macrophage Colony-Stimulating Factor / genetics*
  • Recurrence
  • Reed-Sternberg Cells / drug effects
  • Reed-Sternberg Cells / metabolism*
  • Reed-Sternberg Cells / pathology
  • Survival Analysis
  • Treatment Outcome

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • Biomarkers, Tumor
  • CD68 antigen, human
  • RNA, Messenger
  • Receptor, Macrophage Colony-Stimulating Factor