Gene Expression Profiling on Matched Neurofibroma/MPNST Pairs
Thomas Stricker, Kammi Henriksen, Anthony Montag, Thomas Krausz, Peter Pytel. University of Chicago, Chicago, IL
Background: In the setting of neurofibromatosis type 1 (NF1) a clear malignant transformation from preexisting benign neurofibroma into malignant peripheral nerve sheath tumor (MPNST) is well documented. In NF1 these tumors therefore allow the study of biologic factors important for this malignant transformation.
Design: We selected 12 cases of MPNSTs arising within pre-existing plexiform neurofibromas. For each case RNA was isolated from formalin fixed paraffin embedded neurofibroma and the matched MPNST. The resulting 24 samples were used to analyze the expression of 519 kinase genes using Nanostring nCounter technology. Expresssion was normalized across samples using a generalized linear model framework, and the log 2 transformed residuals from this model were used for subsequent analysis. Differentially expressed kinases between neurofibromas and MPNSTs as a group were assessed by Wilcox test, followed by correction for multiple testing using false discovery rate. Differential expression between NF and MPNST within an individual was assessed by fold change.
Results: Principle component analysis of kinase expression demonstrates that differential expression of kinase genes is sufficient to separate most of MPNSTs from neurofibromas. Interestingly, two of the MPNSTs clustered more closely with neurofibromas than the remaining MPNSTs despite the fact that their histology was not low-grade. The neurofibromas formed a much tighter cluster, while MPNSTs were more heterogenous. 135 genes were differentially expressed at a FDR of 5%. Pathway analysis of differentially expressed genes shows that kinases involved in MAP kinase signaling pathways and kinases involved in the cell cycle, including cyclin dependent kinases and gene involved in chromosomal segregation are upregulated in MPNSTs. Genes that were differentially expressed between neurofibroma and MPNST from the same individual were identified by ranking fold changes. Although there was extensive diversity in these lists, reflecting the diversity of MPNSTs, a few common genes were apparent. The most common upregulated gene was NTRK1, which was upregulated in 9/12 MPNSTs.
Conclusions: In the performed analysis neurofibromas are relatively similar in their expression patterns while MPNSTs exhibit significant diversity. This diversity suggests that even MPNSTs arising in the well defined setting of a plexiform neurofibroma in NF1 are still a quite heterogenous group of tumors. Components of the MAP kinase signaling pathway, NTRK1 and factors involved in chromosomal segregation were upregulated in MPNSTs.
Tuesday, March 20, 2012 2:00 PM
Platform Session: Section F, Tuesday Afternoon