Expression profiling of 519 kinase genes in matched malignant peripheral nerve sheath tumor/plexiform neurofibroma samples is discriminatory and identifies mitotic regulators BUB1B, PBK and NEK2 as overexpressed with transformation

Abstract

About 50% of all malignant peripheral nerve sheath tumors (MPNSTs) arise as neurofibromatosis type 1 associated lesions. In those patients malignant peripheral nerve sheath tumors are thought to arise through malignant transformation of a preexisting plexiform neurofibroma. The molecular changes associated with this transformation are still poorly understood. We sought to test the hypothesis that dysregulation of expression of kinases contributes to this malignant transformation. We analyzed expression of all 519 kinase genes in the human genome using the nanostring nCounter system. Twelve cases of malignant peripheral nerve sheath tumor arising in a background of preexisting plexiform neurofibroma were included. Both components were separately sampled. Statistical analysis compared global changes in expression levels as well as changes observed in the pairwise comparison of samples taken from the same surgical specimen. Immunohistochemical studies were performed on tissue array slides to confirm expression of selected proteins. The expression pattern of kinase genes can separate malignant peripheral nerve sheath tumors and preexisting plexiform neurofibromas. The majority of kinase genes is downregulated rather than overexpressed with malignant transformation. The patterns of expression changes are complex without simple recurring alteration. Pathway analysis demonstrates that differentially expressed kinases are enriched for kinases involved in the direct regulation of mitosis, and several of these show increased expression in malignant peripheral nerve sheath tumors. Immunohistochemical studies for the mitotic regulators BUB1B, PBK and NEK2 confirm higher expression levels at the protein level. These results suggest that the malignant transformation of plexiform neurofibroma is associated with distinct changes in the expression of kinase genes. The patterns of these changes are complex and heterogeneous. There is no single unifying alteration. Kinases involved in mitotic regulation are particularly enriched in the pool of differentially expressed kinases. Some of these are overexpressed and are therefore possible targets for kinase inhibitors.

Overexpression of the Nek2 kinase in colorectal cancer correlates with beta-catenin relocalization and shortened cancer-specific survival

“…Similarly, in the first systematic examination of Nek2 protein expression in CRC to date, we confirmed that Nek2 was overexpressed in 86.4% of resected CRC, with expression correlating with advancing AJCC stage and poor prognosis, and being maintained at secondary sites. These findings are in line with data for other solid and haematological malignancies and highlight Nek2 as a frequently overexpressed protein in human cancer .…”

“…The current study demonstrated correlations between Nek2 protein expression and tumour stage and prognosis in CRC, similar to findings reported for several other malignancies . The association of Nek2 with aggressive tumour biology is, therefore, a recurrent finding.…”

Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival

“…(17;18) For example, expression profiling in matched malignant peripheral nerve sheath tumors and neurofibroma samples did identify more than 500 kinase genes that are differentially expressed between both entities, with mitotic regulators BUB1B , PBK and NEK2 being overexpressed in malignant peripheral nerve sheath tumors. (19) However, the patterns of these changes turned out to be complex and heterogeneous, without a single unifying alteration that could be used as a diagnostic marker. In contrast, staining for H3K27me3 seems to be a more promising and easy to use diagnostic tool, in which loss of H3K27me3 favours progression to malignant peripheral nerve sheath tumors above plexiform or atypical neurofibroma.…”

Nek2A/SuFu feedback loop regulates Gli-mediated Hedgehog signaling pathway

“…The bioinformatic analysis revealed that Nek2 may directly or indirectly interact with a number of genes, proteins, microRNAs associated with drug resistance in ovarian and other types of cancer (28). Aberrant Nek2 expression has also been found in other cancers, such as non-small cell lung cancer and malignant peripheral nerve sheath tumor (29,30). …”