Molecular profiling of malignant peripheral nerve sheath tumors associated with neurofibromatosis type 1, based on large-scale real-time RT-PCR

Abstract

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a complex range of clinical symptoms. The hallmark of NF1 is the onset of heterogeneous (dermal or plexiform) benign neurofibromas. Plexiform neurofibromas can give rise to malignant peripheral nerve sheath tumors (MPNSTs), and the underlying molecular mechanisms are largely unknown.

Results: To obtain further insight into the molecular pathogenesis of MPNSTs, we used real-time quantitative RT-PCR to quantify the mRNA expression of 489 selected genes in MPNSTs, in comparison with plexiform neurofibromas. The expression of 28 (5.7%) of the 489 genes was significantly different between MPNSTs and plexiform neurofibromas; 16 genes were upregulated and 12 were downregulated in MPNSTs. The altered genes were mainly involved in cell proliferation (MKI67, TOP2A, CCNE2), senescence (TERT, TERC), apoptosis (BIRC5/Survivin, TP73) and extracellular matrix remodeling (MMP13, MMP9, TIMP4, ITGB4). More interestingly, other genes were involved in the Ras signaling pathway (RASSF2, HMMR/RHAMM) and the Hedgehog-Gli signaling pathway (DHH, PTCH2). Several of the down-regulated genes were Schwann cell-specific (L1CAM, MPZ, S100B, SOX10, ERBB3) or mast cell-specific (CMA1, TPSB), pointing to a depletion and/or dedifferentiation of Schwann cells and mast cells during malignant transformation of plexiform neurofibromas.

Conclusion: These data suggest that a limited number of signaling pathways, and particularly the Hedgehog-Gli signaling pathway, may be involved in malignant transformation of plexiform neurofibromas. Some of the relevant genes or their products warrant further investigation as potential therapeutic targets in NF1.

Figure 1

mRNA levels of MKI67, BIRC5/Survivin and SPP1 in 10 individual dermal neurofibromas (white bars), 14 plexiform neurofibromas (gray bars) and 9 MPNSTs (black bars). Median values (and ranges) are indicated for each tumor subgroup.

Figure 2

mRNA levels of ITGB4, CMA1/Chymase 1 and L1CAM in 10 individual dermal neurofibromas (white bars), 14 plexiform neurofibromas (gray bars) and 9 MPNSTs (black bars). Median values (and ranges) are indicated for each tumor subgroup.

Figure 3

Expression level of various genes in the dermal neurofibroma pool (white bars), the plexiform neurofibroma pool (gray bars) and the MPNST pool (black bars). A, ERBB family member genes; B, matrix metalloproteinase genes; C, inhibitor of metalloproteinase genes; D, chemokine genes; E, Ras signaling pathway genes; F, Hedgehog-Gli signaling pathway genes; G, Gli-regulated genes.