title: Gene expression profiling of microdissected Hodgkin Reed-Sternberg cells correlates with treatment outcome in classical Hodgkin lymphoma.
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.
authors.affiliation: Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada. csteidl@bccancer.bc.ca
authors.forename: Christian
authors.initials: C
authors.lastname: Steidl
authors.forename: Arjan
authors.initials: A
authors.lastname: Diepstra
authors.forename: Tang
authors.initials: T
authors.lastname: Lee
authors.forename: Fong Chun
authors.initials: FC
authors.lastname: Chan
authors.forename: Pedro
authors.initials: P
authors.lastname: Farinha
authors.forename: King
authors.initials: K
authors.lastname: Tan
authors.forename: Adele
authors.initials: A
authors.lastname: Telenius
authors.forename: Lorena
authors.initials: L
authors.lastname: Barclay
authors.forename: Sohrab P
authors.initials: SP
authors.lastname: Shah
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Connors
authors.forename: Anke
authors.initials: A
authors.lastname: van den Berg
authors.forename: Randy D
authors.initials: RD
authors.lastname: Gascoyne
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics*; D045744:Cell Line, Tumor; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006689:Hodgkin Disease / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D017403:In Situ Hybridization; D061346:Laser Capture Microdissection; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000096:biosynthesis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics*; D012008:Recurrence; D016539:Reed-Sternberg Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; D016186:Receptor, Macrophage Colony-Stimulating Factor; C067980:CD68 antigen, human; D000097382:CD68 Molecule