Molecular profiles of neurofibromatosis type 1-associated plexiform neurofibromas: identification of a gene expression signature of poor prognosis.
OBJECTIVE
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex variety of clinical symptoms. The hallmark of NF1 is the development of heterogeneous benign neurofibromas, which may appear as dermal neurofibromas or plexiform neurofibromas. NF1 patients with plexiform neurofibromas are at risk of developing malignant peripheral nerve sheath tumors.


METHODS
To obtain additional insight into the molecular pathogenesis of plexiform neurofibromas, we used real-time quantitative reverse transcription-PCR assays to quantify the mRNA expression of 349 selected genes in plexiform neurofibromas in comparison with dermal neurofibromas and patient-matched malignant peripheral nerve sheath tumors.


RESULTS
Thirty genes were significantly up-regulated in plexiform neurofibromas compared with dermal neurofibromas. None were down-regulated. The up-regulated genes mainly encoded transcription factors and growth factors and secreted proteins, cytokines, and their receptors, pointing to a role of paracrine and autocrine signaling defects in the genesis of plexiform neurofibromas. We also identified a gene expression profile, based on MMP9, FLT4/VEGFR3, TNFRSF10B/TRAILR2, SHH, and GLI1, which discriminated those plexiform neurofibromas most likely to undergo malignant transformation.


CONCLUSIONS
Our study has identified a limited number of signaling pathways that could be involved, when altered, in plexiform neurofibroma development. Some of the up-regulated genes could be useful diagnostic or prognostic markers or form the basis of novel therapeutic strategies.
Lévy
Pascale
P
Laboratoire de Génétique Moléculaire - UPRES EA 3618, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, Paris.
Bièche
Ivan
I
Leroy
Karen
K
Parfait
Béatrice
B
Wechsler
Janine
J
Laurendeau
Ingrid
I
Wolkenstein
Pierre
P
Vidaud
Michel
M
Vidaud
Dominique
D
D000293:Adolescent; D000328:Adult; D002471:Cell Transformation, Neoplastic; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D018317:Nerve Sheath Neoplasms / Q000235:genetics*; D009455:Neurofibroma / Q000473:pathology*; D018318:Neurofibroma, Plexiform / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000235:genetics*; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D015854:Up-Regulation
D017931:DNA Primers; D012333:RNA, Messenger; D012313:RNA