title: Fibroblast growth factor-2 (FGF2) and syndecan-1 (SDC1) are potential biomarkers for putative circulating CD15+/CD30+ cells in poor outcome Hodgkin lymphoma patients.
abstract: BACKGROUND
  High risk, unfavorable classical Hodgkin lymphoma (cHL) includes those patients with primary refractory or early relapse, and progressive disease. To improve the availability of biomarkers for this group of patients, we investigated both tumor biopsies and peripheral blood leukocytes (PBL) of untreated (chemo-naïve, CN) Nodular Sclerosis Classic Hodgkin Lymphoma (NS-cHL) patients for consistent biomarkers that can predict the outcome prior to frontline treatment.
  
  
  METHODS
  Bioinformatics data mining was used to generate 151 candidate biomarkers, which were screened against a library of 10 HL cell lines. Expression of FGF2 and SDC1 by CD30+ cells from HL patient samples representing good and poor outcomes were analyzed by qRT-PCR, immunohistochemical (IHC), and immunofluorescence analyses.
  
  
  RESULTS
  To identify predictive HL-specific biomarkers, potential marker genes selected using bioinformatics approaches were screened against HL cell lines and HL patient samples. Fibroblast Growth Factor-2 (FGF2) and Syndecan-1 (SDC1) were overexpressed in all HL cell lines, and the overexpression was HL-specific when compared to 116 non-Hodgkin lymphoma tissues. In the analysis of stratified NS-cHL patient samples, expression of FGF2 and SDC1 were 245 fold and 91 fold higher, respectively, in the poor outcome (PO) group than in the good outcome (GO) group. The PO group exhibited higher expression of the HL marker CD30, the macrophage marker CD68, and metastatic markers TGFβ1 and MMP9 compared to the GO group. This expression signature was confirmed by qualitative immunohistochemical and immunofluorescent data. A Kaplan-Meier analysis indicated that samples in which the CD30+ cells carried an FGF2+/SDC1+ immunophenotype showed shortened survival. Analysis of chemo-naive HL blood samples suggested that in the PO group a subset of CD30+ HL cells had entered the circulation. These cells significantly overexpressed FGF2 and SDC1 compared to the GO group. The PO group showed significant down-regulation of markers for monocytes, T-cells, and B-cells. These expression signatures were eliminated in heavily pretreated patients.
  
  
  CONCLUSIONS
  The results suggest that small subsets of circulating CD30+/CD15+ cells expressing FGF2 and SDC1 represent biomarkers that identify NS-cHL patients who will experience a poor outcome (primary refractory and early relapsing).
authors.affiliation: John Theurer Cancer Center, Hackensack University Medical Center, D, Jurist Research Building, 40 Prospect Avenue, Hackensack, NJ 07601, USA. ksuh@hackensackUMC.org.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Gharbaran
authors.forename: Andre
authors.initials: A
authors.lastname: Goy
authors.forename: Takemi
authors.initials: T
authors.lastname: Tanaka
authors.forename: Jongwhan
authors.initials: J
authors.lastname: Park
authors.forename: Chris
authors.initials: C
authors.lastname: Kim
authors.forename: Nafis
authors.initials: N
authors.lastname: Hasan
authors.forename: Swathi
authors.initials: S
authors.lastname: Vemulapalli
authors.forename: Sreeja
authors.initials: S
authors.lastname: Sarojini
authors.forename: Madalina
authors.initials: M
authors.lastname: Tuluc
authors.forename: Kip
authors.initials: K
authors.lastname: Nalley
authors.forename: Pritish
authors.initials: P
authors.lastname: Bhattacharyya
authors.forename: Andrew
authors.initials: A
authors.lastname: Pecora
authors.forename: K Stephen
authors.initials: KS
authors.lastname: Suh
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism*; D005647:Fucosyltransferases / Q000378:metabolism*; D006689:Hodgkin Disease / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D017730:Ki-1 Antigen / Q000378:metabolism*; D016256:Lewis X Antigen / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009360:Neoplastic Cells, Circulating / Q000378:metabolism*; D012189:Retrospective Studies; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D017730:Ki-1 Antigen; D016256:Lewis X Antigen; C508241:SDC1 protein, human; D053668:Syndecan-1; D016222:Fibroblast Growth Factor 2; C066693:FUT4 protein, human; D005647:Fucosyltransferases