title: Serum biomarkers for neurofibromatosis type 1 and early detection of malignant peripheral nerve-sheath tumors.
abstract: BACKGROUND
  Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome characterized by the development of benign nerve-sheath tumors, which transform to malignant peripheral nerve-sheath tumors (MPNST) in about 8 to 13% of patients with NF1. MPNST are invasive sarcomas with extremely poor prognosis, and their development may correlate with internal tumor load of patients with NF1. Because early identification of patients with NF1 at risk for developing MPNST should improve their clinical outcome, the aim of this study was to identify serum biomarkers for tumor progression in NF1, and to analyze their correlation with tumor type and internal tumor load.
  
  
  METHODS
  We selected candidate biomarkers for NF1 by manually mining published data sources, and conducted a systematic screen of 56 candidate serum biomarkers using customized antibody arrays. Serum from 104 patients with NF1 with and without MPNST, and from 41 healthy control subjects, was analyzed. Statistical analysis was performed using the non-parametric Mann-Whitney U-test, followed by Bonferroni correction.
  
  
  RESULTS
  Our analysis identified four markers (epidermal growth factor receptor, interferon-γ, interleukin-6, and tumor necrosis factor-α) for which significantly different serum concentrations were seen in patients with NF1 compared with healthy controls. Two markers (insulin-like growth factor binding protein 1 (IGFBP1) and regulated upon activation, normal T-cell expressed and secreted (RANTES)) showed significantly higher concentrations in patients with NF1 and MPNST compared with patients with NF1 without MPNST. A correlation with internal tumor load was found for IGFBP1.
  
  
  CONCLUSIONS
  Our study identified two serum markers with potential for early detection of patients with NF1 at risk for developing MPNST, and four markers that could distinguish between patients with NF1 and healthy subjects. Such markers may be useful as diagnostic tools to support the diagnosis of NF1 and for timely identification of MPNST. Moreover, the data suggest that there is a systemic increase in inflammatory cytokines independently of tumor load in patients with NF1.
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, 13353, Germany.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Birgit
authors.initials: B
authors.lastname: Sawitzki
authors.forename: Lan
authors.initials: L
authors.lastname: Kluwe
authors.forename: Victor F
authors.initials: VF
authors.lastname: Mautner
authors.forename: Nikola
authors.initials: N
authors.lastname: Holtkamp
authors.forename: Andreas
authors.initials: A
authors.lastname: Kurtz
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000097:blood*; D002648:Child; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018317:Nerve Sheath Neoplasms / Q000175:diagnosis*; D009456:Neurofibromatosis 1 / Q000150:complications* / Q000175:diagnosis*; D044967:Serum / Q000737:chemistry; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor