Gene expression analysis identifies potential biomarkers of neurofibromatosis type 1 including adrenomedullin.
OBJECTIVE
Plexiform neurofibromas (pNF) are Schwann cell tumors found in a third of individuals with neurofibromatosis type 1 (NF1). pNF can undergo transformation to malignant peripheral nerve sheath tumors (MPNST). There are no identified serum biomarkers of pNF tumor burden or transformation to MPNST. Serum biomarkers would be useful to verify NF1 diagnosis, monitor tumor burden, and/or detect transformation.


METHODS
We used microarray gene expression analysis to define 92 genes that encode putative secreted proteins in neurofibroma Schwann cells, neurofibromas, and MPNST. We validated differential expression by quantitative reverse transcription-PCR, Western blotting, and ELISA assays in cell conditioned medium and control and NF1 patient sera.


RESULTS
Of 13 candidate genes evaluated, only adrenomedullin (ADM) was confirmed as differentially expressed and elevated in serum of NF1 patients. ADM protein concentrati on was further elevated in serum of a small sampling of NF1 patients with MPNST. MPNST cell conditioned medium, containing ADM and hepatocyte growth factor, stimulated MPNST migration and endothelial cell proliferation.


CONCLUSIONS
Thus, microarray analysis identifies potential serum biomarkers for disease, and ADM is a serum biomarker of NF1. ADM serum levels do not seem to correlate with the presence of pNFs but may be a biomarker of transformation to MPNST.
Hummel
Trent R
TR
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.
Jessen
Walter J
WJ
Miller
Shyra J
SJ
Kluwe
Lan
L
Mautner
Victor F
VF
Wallace
Margaret R
MR
Lázaro
Conxi
C
Page
Grier P
GP
Worley
Paul F
PF
Aronow
Bruce J
BJ
Schorry
Elizabeth K
EK
Ratner
Nancy
N
D000293:Adolescent; D053607:Adrenomedullin / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D000328:Adult; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D002465:Cell Movement / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D003470:Culture Media; D042783:Endothelial Cells / Q000166:cytology; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009456:Neurofibromatosis 1 / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D015203:Reproducibility of Results; D012583:Schwann Cells / Q000473:pathology; D055815:Young Adult
D014408:Biomarkers, Tumor; D003470:Culture Media; D012333:RNA, Messenger; D053607:Adrenomedullin