Association between benign and malignant peripheral nerve sheath tumors in NF1

Tucker, Tracy; Wolkenstein, Pierre; Revuz, J; Zeller, J; Friedman, Jan M.

doi:10.1212/01.wnl.0000168830.79997.13

Cited by 268 publications

(186 citation statements)

References 31 publications

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“…For each gene, P-values were calculated by Wilcoxon rank sum test, and false discovery rates were estimated by Storey's q-value method. 23 (2) Pairwise examination of the matched samples from the same case was performed to look for expression changes. For pairwise analysis, all samples were retained and corrected, and empirical Bayes t-tests, using limma, were performed for each individual, comparing plexiform neurofibroma with malignant peripheral nerve sheath tumor.…”

Section: Gene Expression Analysis-combined Sample Set and Pairwise Comentioning

confidence: 99%

“…The other half are neurofibromatosis type 1 (NF1) associated and develop through malignant transformation of a preexisting plexiform neurofibroma. 1,2 Malignant peripheral nerve sheath tumors often show complex karyotypes with losses and gains of chromosome arms as well as focal amplifications and deletions. [3][4][5][6] A number of miRNAs, cell cycle regulators, signaling molecules and transcription factors have been shown to be differentially expressed between neurofibromas and malignant peripheral nerve sheath tumors including CDKN2A, TP53, RB1, EGFR, CD44, PDGFRB, PDGFRA, HGF, MET, IGFR1, SOX9, SOX10, miR-34a and miR-21.…”

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confidence: 99%

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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

et al. 2013

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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.

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Section: Gene Expression Analysis-combined Sample Set and Pairwise Comentioning

confidence: 99%

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confidence: 99%

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

et al. 2013

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“…Individuals with subcutaneous neurofibromas are approximately three times more likely to have internal plexiform neurofibromas or MPNSTs than Nf1 sufferers with no subcutaneous lesions. 18 These individuals warrant increased surveillance for MPNST as well as patients with plexiform neurofibromas in the brachial or lumbosacral plexus, a history of radiotherapy, a personal or family history of malignancy and Nf1 patients harbouring microdeletions of the Nf1 gene. 9 Persistent pain, change in texture, rapid increase in size and neurological deficit associated with a neurofibroma are clinical features of malignancy ( Figure 4).…”

Section: Description Of Disease Manifestationsmentioning

confidence: 99%

Neurofibromatosis 1

2006

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Neurofibromatosis 1 predisposes affected individuals to the development of benign and malignant tumours that are frequently disfiguring and difficult to manage. However, advances in molecular biology and the development of mouse models have facilitated our understanding of disease pathogenesis. Positron emission tomography has demonstrated that sophisticated imaging techniques have a role in diagnosing complex problems like malignant peripheral nerve sheath tumours, while the prospect of targeted therapies for Nf1 complications is tantalisingly close.

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“…21 Individuals affected with NF1 have a 2 to 5% risk of malignant transformation of their plexiform neurofibroma. 1,11,28,48 Malignant PNSTs or neurofibrosarcomas are the main lesions that result from malignant transformation. These lesions often occur during adolescence and young adulthood.…”

Section: Neurological Manifestationsmentioning

confidence: 99%

“…The 5-year survival of patients with malignant PNSTs is approximately 40%. 28,48 The general treatment of malignant PNSTs includes diagnostic biopsy sampling followed by extensive excision to achieve wide margin resection, radiation, and chemotherapy.…”

Section: Neurological Manifestationsmentioning

confidence: 99%

J. Lawrence Pool, M.D.: a pioneer in vascular neurosurgery

Zacharia

Mocco

Komotar

et al. 2006

FOC

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Neurofibromatosis Type 1 (NF1) is one of the most common inherited diseases in humans. It is caused by a mutation in the NF1 gene on chromosome 17, and is associated with numerous central and peripheral nervous system manifestations. Children with NF1 are at high risk of harboring numerous lesions that may require the attention of a neurosurgeon. Some of these include optic nerve gliomas, hydrocephalus, intraspinal tumors, and peripheral nerve tumors. Although most of the neoplasms that affect the brain, spine, and peripheral nerves of children are low-grade lesions, there is a small but real risk that some of these lesions may become high grade over time, requiring other forms of therapy than surgery alone. Other associated disorders that may result from NF1 in childhood include Chiari malformation Type I, scoliosis, and pulsating exophthalmos from the absence of the sphenoid wing. In this review, the major lesions that are found in children with NF1 are reviewed as well as the types of treatment that are offered by neurosurgeons and other members of the treating team. Today, optimum care of the child with NF1 is provided by a multidisciplinary team comprising neurosurgeons, neurologists, ophthalmologists, radiologists, orthopedic surgeons, and plastic surgeons.

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Association between benign and malignant peripheral nerve sheath tumors in NF1

Abstract: The observation that malignant peripheral nerve sheath tumors are strongly associated with internal plexiform neurofibromas suggests that patients with neurofibromatosis type 1 with these benign tumors warrant increased surveillance for malignancy.

Cited by 268 publications

References 31 publications

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

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

Neurofibromatosis 1

J. Lawrence Pool, M.D.: a pioneer in vascular neurosurgery

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