LMNA-NTRK1 rearranged mesenchymal tumor (lipofibromatosis-like neural tumor) mimicking pigmented dermatofibrosarcoma protuberans.

We present the case of a 31-year-old female with a 1.5 cm pigmented nodule on the scalp. Histopathological examination revealed a proliferation of relatively bland spindle cells and pigmented dendritic cells, with interspersed lymphoid follicles diffusely infiltrating the adipose tissue. The microscopic differential diagnosis included pigmented dermatofibrosarcoma protuberans (DFSP). The spindle cells showed S-100 and CD34 labeling but were negative for SOX-10. Immunohistochemical stain for pan-TRK was positive, while fluorescence in-situ hybridization for PDGFB gene rearrangement was negative. Targeted RNA sequencing revealed an LMNA-NTRK1 (exon2/exon10) fusion. This molecular result coupled with the histopathological findings and immunohistochemical profile supported the diagnosis of the recently characterized NTRK-rearranged spindle cell neoplasm termed "lipofibromatosis-like neural tumor (LPF-NT)." These neoplasms typically occur in superficial soft tissue and are characterized by a distinctive immunoprofile (CD34+, S-100+, SOX10-). Histopathological differential diagnosis for LPF-NT tumors includes lipofibromatosis, DFSP, low-grade malignant peripheral nerve sheath tumor, and spindle cell/desmoplastic melanoma. The pigmented dendritic cells reminiscent of pigmented DFSP and lymphoid follicles noted in our case have not been previously reported in LPF-NT, thus expanding the morphological spectrum of this entity. LMNA-NTRK1 fusion serves both as a diagnostic and therapeutic biomarker, as cases with advanced disease may be amenable to targeted therapy using tyrosine kinase inhibitors.

Multinodular and vacuolating neuronal tumors in epilepsy: dysplasia or neoplasia?

Multinodular and vacuolating neuronal tumor (MVNT) is a new pattern of neuronal tumour included in the recently revised WHO 2016 classification of tumors of the CNS. There are 15 reports in the literature to date. They are typically associated with late onset epilepsy and a neoplastic vs. malformative biology has been questioned. We present a series of ten cases and compare their pathological and genetic features to better characterized epilepsy-associated malformations including focal cortical dysplasia type II (FCDII) and low-grade epilepsy-associated tumors (LEAT). Clinical and neuroradiology data were reviewed and a broad immunohistochemistry panel was applied to explore neuronal and glial differentiation, interneuronal populations, mTOR pathway activation and neurodegenerative changes. Next generation sequencing was performed for targeted multi-gene analysis to identify mutations common to epilepsy lesions including FCDII and LEAT. All of the surgical cases in this series presented with seizures, and were located in the temporal lobe. There was a lack of any progressive changes on serial pre-operative MRI and a mean age at surgery of 45 years. The vacuolated cells of the lesion expressed mature neuronal markers (neurofilament/SMI32, MAP2, synaptophysin). Prominent labelling of the lesional cells for developmentally regulated proteins (OTX1, TBR1, SOX2, MAP1b, CD34, GFAPδ) and oligodendroglial lineage markers (OLIG2, SMI94) was observed. No mutations were detected in the mTOR pathway genes, BRAF, FGFR1 or MYB. Clinical, pathological and genetic data could indicate that MVNT aligns more with a malformative lesion than a true neoplasm with origin from a progenitor neuro-glial cell type showing aberrant maturation.

Glycolipids: Essential regulator of neuro-inflammation, metabolism and gliomagenesis.

Gene knockout mice of glycosyltransferases have clearly showed roles of their products in the bodies, while there are examples where phenotype of knockout was much less severe than expected probably due to functional redundancy. The most striking novel finding obtained from ganglioside-deficient mice was that progressive inflammatory reaction took place, leading to neurodegeneration. In particular, dysfunction of complement-regulatory proteins due to deteriorated architecture of lipid rafts seemed to be essential mechanisms for the inflammation. Furthermore, roles of gangliosides in neurons were demonstrated by neuron-specific transgenic of B4galnt1 with genetic background of B4galnt1 deficiency. From study of gene knockout mice of St8sia1, new roles of b-series gangliosides in leptin secretion from adipocytes, and roles of a-series gangliosides in leptin receptor, ObR in hypothalamus were demonstrated, leading to apparent intact balance of energy. Essential roles of b-series gangliosides in malignant properties of gliomas were also shown, suggesting their roles in the regulation of inflammation and proliferation in nervous tissues. How to apply these findings for the control of newly discovered patients with ganglioside deficiency remains to be investigated. This article is part of a Special Issue entitled Neuro-glycoscience, edited by Kenji Kadomatsu and Hiroshi Kitagawa.

Glomus-like bodies within a neurofibroma: a novel neoplasm arising in neurofibromatosis type 1 or a coincidence?

Neurofibromatosis type 1 is a relatively common genetic disorder with variable phenotypes. Tumors with features of both glomus tumors and neurofibromas are exceedingly rare in literature. Herein, we report a not yet described neoplasm with features of both a glomangioma/glomus tumor and a neurofibroma arising in a patient with segmental neurofibromatosis. Our case report supports the theory of a common lineage/ancestor cell between neurofibromas and glomus tumors and adds it to the spectrum of neoplasms that may arise in the setting of Von Recklinghausen's disease.

Braided pattern in a dermatofibrosarcoma protuberans: a potential mimicker of neural neoplasms.

Dermatofibrosarcoma protuberans (DFSP) is a dermal and subcutaneous slow-growing tumor of intermediate malignancy. Different histological variants of DFSP have been described, depending on cellular and stromal peculiarities. Here, we report the histological features of a DFSP in which cells were frequently arrayed in cords and fascicles that were interweaved, conforming a peculiar braided pattern. This finding might pose difficulties in the differential diagnosis with neural neoplasms and expands the morphological spectrum of DFSP.

Defining key signaling nodes and therapeutic biomarkers in NF1-mutant cancers.

UNLABELLED: NF1 encodes a RAS GTPase-activating protein. Accordingly, aberrant RAS activation underlies the pathogenesis of NF1-mutant cancers. Nevertheless, it is unclear which RAS pathway components represent optimal therapeutic targets. Here, we identify mTORC1 as the key PI3K effector in NF1-mutant nervous system malignancies and conversely show that mTORC2 and AKT are dispensable. However, we find that tumor regression requires sustained inhibition of both mTORC1 and MEK. Transcriptional profiling studies were therefore used to establish a signature of effective mTORC1-MEK inhibition in vivo. We unexpectedly found that the glucose transporter GLUT1 was potently suppressed, but only when both pathways were inhibited. Moreover, unlike VHL- and LKB1-mutant cancers, reduction of (18)F-FDG uptake required the suppression of both mTORC1 and MEK. Together, these studies identify optimal and suboptimal therapeutic targets in NF1-mutant malignancies and define a noninvasive means of measuring combined mTORC1-MEK inhibition in vivo, which can be readily incorporated into clinical trials. SIGNIFICANCE: This work demonstrates that mTORC1 and MEK are key therapeutic targets in NF1-mutant cancers and establishes a noninvasive biomarker of effective, combined target inhibition that can be evaluated in clinical trials.

Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge.

We have extended our understanding of the molecular biology that underlies adult glioblastoma over many years. By contrast, high-grade gliomas in children and adolescents have remained a relatively under-investigated disease. The latest large-scale genomic and epigenomic profiling studies have yielded an unprecedented abundance of novel data and provided deeper insights into gliomagenesis across all age groups, which has highlighted key distinctions but also some commonalities. As we are on the verge of dissecting glioblastomas into meaningful biological subgroups, this Review summarizes the hallmark genetic alterations that are associated with distinct epigenetic features and patient characteristics in both paediatric and adult disease, and examines the complex interplay between the glioblastoma genome and epigenome.

Mutations affecting BRAF, EGFR, PIK3CA, and KRAS are not associated with sporadic vestibular schwannomas.

Sporadic vestibular schwannomas are benign tumors originating from the Schwann cells of the vestibular portion of the eigth cranial nerve. An important clinical hallmark of these tumors is their variable growth rate. Investigating vestibular schwannoma biology can help to clarify this variable growth rate and may offer targets for therapeutic treatment. A recent mutation analysis on sporadic non-head and neck schwannomas detected BRAF mutations in around 20 % of tumors. BRAF is part of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway. MAPK/ERK activation is associated with an uncontrolled cell growth. Mutated BRAF can function as a target to inhibit this pathway. Mutations in BRAF and other members of the MAPK/ERK pathway have not been investigated in sporadic vestibular schwannomas before. The goal of this study was to investigate if these mutations are present in vestibular schwannomas and whether these mutations correlate with tumor growth. Tumor specimens of 48 patients surgically treated for a sporadic vestibular schwannoma were analyzed. An allele-specific quantitative real-time PCR assay was performed to detect the 13 most frequent mutations affecting BRAF, EGFR, PIK3CA, and KRAS. Radiologically measured tumor growth was included in the analysis to identify potential relationships between these mutations and tumor progression. No activating hotspot mutations in BRAF, EGFR, PIK3CA, or KRAS were detected. The 13 most frequent mutations affecting BRAF, EGFR, PIK3CA, and KRAS are not involved in sporadic vestibular schwannoma development. These results are in contrast to the recent detection of these BRAF mutations in non-head and neck schwannomas.

From sets to graphs: towards a realistic enrichment analysis of transcriptomic systems.

MOTIVATION: Current gene set enrichment approaches do not take interactions and associations between set members into account. Mutual activation and inhibition causing positive and negative correlation among set members are thus neglected. As a consequence, inconsistent regulations and contextless expression changes are reported and, thus, the biological interpretation of the result is impeded. RESULTS: We analyzed established gene set enrichment methods and their result sets in a large-scale investigation of 1000 expression datasets. The reported statistically significant gene sets exhibit only average consistency between the observed patterns of differential expression and known regulatory interactions. We present Gene Graph Enrichment Analysis (GGEA) to detect consistently and coherently enriched gene sets, based on prior knowledge derived from directed gene regulatory networks. Firstly, GGEA improves the concordance of pairwise regulation with individual expression changes in respective pairs of regulating and regulated genes, compared with set enrichment methods. Secondly, GGEA yields result sets where a large fraction of relevant expression changes can be explained by nearby regulators, such as transcription factors, again improving on set-based methods. Thirdly, we demonstrate in additional case studies that GGEA can be applied to human regulatory pathways, where it sensitively detects very specific regulation processes, which are altered in tumors of the central nervous system. GGEA significantly increases the detection of gene sets where measured positively or negatively correlated expression patterns coincide with directed inducing or repressing relationships, thus facilitating further interpretation of gene expression data. AVAILABILITY: The method and accompanying visualization capabilities have been bundled into an R package and tied to a grahical user interface, the Galaxy workflow environment, that is running as a web server. CONTACT: Ludwig.Geistlinger@bio.ifi.lmu.de; Ralf.Zimmer@bio.ifi.lmu.de.

Landscape of the SOX2 protein-protein interactome.

SOX2 is a key gene implicated in maintaining the stemness of embryonic and adult stem cells that appears to re-activate in several human cancers including glioblastoma multiforme. Using immunoprecipitation (IP)/MS/MS, we identified 144 proteins that are putative SOX2 interacting proteins. Of note, SOX2 was found to interact with several heterogeneous nuclear ribonucleoprotein family proteins, including HNRNPA2B1, HNRNPA3, HNRNPC, HNRNPK, HNRNPL, HNRNPM, HNRNPR, HNRNPU, as well as other ribonucleoproteins, DNA repair proteins and helicases. Gene ontology (GO) analysis revealed that the SOX2 interactome was enriched for GO terms GO:0030529 ribonucleoprotein complex and GO:0004386 helicase activity. These findings indicate that SOX2 associates with the heterogeneous nuclear ribonucleoprotein complex, suggesting a possible role for SOX2 in post-transcriptional regulation in addition to its function as a transcription factor.

Neurooncology of familial cancer syndromes.

The majority of tumors of the nervous system are sporadic. However, a subset of patients with tumors and their families are predisposed to developing cancers of the central nervous system and other organs because of a germline mutation. In the last decade, many of the genes responsible for these typically autosomal dominant familial tumor syndromes have been identified. Additionally, our understanding of the mechanisms of carcinogenesis in these syndromes has increased, allowing for more targeted therapies for these patients as well as those with sporadic cancers. Because these patients present a unique set of issues regarding diagnosis and neurooncological management, the most common familial cancer syndromes involving the nervous system are reviewed: neurofibromatosis type 1 and 2; tuberous sclerosis complex; von Hippel Lindau, Li-Fraumeni, Gorlin, and Turcot syndrome.

Cytogenetic findings in a rare pediatric mixed glioneuronal tumor and review of the literature.

OBJECTIVE: The aim of the present study was to report the chromosomal abnormalities findings in rare pediatric mixed glioneuronal tumor (GNT), which could not be classified according to the WHO classification. METHODS: Cytogenetic studies were performed using G-banding and fluorescence in situ hybridization (FISH) techniques. RESULTS: Cytogenetic analyses showed a deletion of 1p as primary genetic event and gain of chromosome 7 as secondary change. Furthermore, we present a review of available cytogenetic data of 72 pediatric patients with GNT. Taken into account these data and the present case, we found that the most frequent chromosomal anomalies involved gains of chromosomes 7 (15.1%), 5 (8.2%), 1q32-qter (6.8%), 8p21-qter (6.8%), 12 (5.5%), 18 (5.5%), 20q11-qter (5.5%), and X (5.5%). Frequent losses were detected on chromosome regions 1p (8.2%) and 22q (5.5%). CONCLUSION: The findings of our case combined with those of previous reports suggest that chromosomes 1 and 7 may contain candidate genes involved in the tumorigenesis of GNT.

Genetic markers of mediastinal tumors.

Determination of the genetic markers by the application of new genomic methodologies has provided important insight into the pathogenesis of mediastinal disease. These new techniques have enabled scientists to uncover differential gene expression patterns between subtypes of thymomas, correlate tumor marker expression with germ cell tumors, and determine a link between the NF-kappaB and JAK/STAT pathways with Hodgkin's and non-Hodgkin's lymphoma. Despite the progress made in the understanding of genetic markers of select mediastinal tumors, significantly more investigation is required to elucidate the molecular pathways involved in the pathogenesis of these tumors.

High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL.

GenoMEL, comprising major familial melanoma research groups from North America, Europe, Asia, and Australia has created the largest familial melanoma sample yet available to characterize mutations in the high-risk melanoma susceptibility genes CDKN2A/alternate reading frames (ARF), which encodes p16 and p14ARF, and CDK4 and to evaluate their relationship with pancreatic cancer (PC), neural system tumors (NST), and uveal melanoma (UM). This study included 466 families (2,137 patients) with at least three melanoma patients from 17 GenoMEL centers. Overall, 41% (n = 190) of families had mutations; most involved p16 (n = 178). Mutations in CDK4 (n = 5) and ARF (n = 7) occurred at similar frequencies (2-3%). There were striking differences in mutations across geographic locales. The proportion of families with the most frequent founder mutation(s) of each locale differed significantly across the seven regions (P = 0.0009). Single founder CDKN2A mutations were predominant in Sweden (p.R112_L113insR, 92% of family's mutations) and the Netherlands (c.225_243del19, 90% of family's mutations). France, Spain, and Italy had the same most frequent mutation (p.G101W). Similarly, Australia and United Kingdom had the same most common mutations (p.M53I, c.IVS2-105A>G, p.R24P, and p.L32P). As reported previously, there was a strong association between PC and CDKN2A mutations (P < 0.0001). This relationship differed by mutation. In contrast, there was little evidence for an association between CDKN2A mutations and NST (P = 0.52) or UM (P = 0.25). There was a marginally significant association between NST and ARF (P = 0.05). However, this particular evaluation had low power and requires confirmation. This GenoMEL study provides the most extensive characterization of mutations in high-risk melanoma susceptibility genes in families with three or more melanoma patients yet available.

Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis.

Benign neurofibromas and malignant peripheral nerve sheath tumors are serious complications of neurofibromatosis type 1. The epidermal growth factor receptor is not expressed by normal Schwann cells, yet is overexpressed in subpopulations of Nf1 mutant Schwann cells. We evaluated the role of EGFR in Schwann cell tumorigenesis. Expression of EGFR in transgenic mouse Schwann cells elicited features of neurofibromas: Schwann cell hyperplasia, excess collagen, mast cell accumulation, and progressive dissociation of non-myelin-forming Schwann cells from axons. Mating EGFR transgenic mice to Nf1 hemizygotes did not enhance this phenotype. Genetic reduction of EGFR in Nf1(+/-);p53(+/-) mice that develop sarcomas significantly improved survival. Thus, gain- and loss-of-function experiments support the relevance of EGFR to peripheral nerve tumor formation.

BRAF as a melanoma susceptibility candidate gene?

A high frequency of activating BRAF somatic mutations have been identified recently in malignant melanoma and nevi indicating that BRAF activation could be an early and critical step in the initiation of melanocytic neoplasia. To determine whether BRAF mutations could be an earlier event occurring at the germline level, we screened the entire BRAF coding region for germline mutations in 80 independent melanoma-prone families or patients with multiple primary melanoma without a familial history. We identified 13 BRAF variants, 4 of which were silent mutations in coding regions and 9 nucleotide substitutions in introns. None of these BRAF variants segregated with melanoma in the 11 melanoma families studied. Moreover, there was no significant difference in the frequency of heterozygotes for BRAF variants between melanoma cases and controls when they were compared. Our data suggest that BRAF is unlikely to be a melanoma susceptibility gene.

Mutations in exon 11 of the c-kit gene in a myogenic tumor and a neurogenic tumor as well as in gastrointestinal stromal tumors. Utility of c-kit mutation as a prognostic biomarker for gastrointestinal mesenchymal tumor.

BACKGROUND/AIMS: Gain-of-function mutations in exons 9, 11 and 13 of the c-kit gene in gastrointestinal stromal tumors (GISTs) have been identified, and it has been reported that the prognosis is worse for patients with mutation-positive GISTs than for those with mutation-negative GISTs. We studied c-kit mutations in gastrointestinal mesenchymal tumors. By chance, the c-kit mutation in exon 11 was found in myogenic and neurogenic tumors as well as in GISTs. Furthermore, we studied the clinical prognostic utility of these mutations. METHODS: Ten gastrointestinal mesenchymal tumors were stained with HE and immunohistochemically analyzed with alpha-smooth muscle actin, S-100 protein, CD34 and c-kit. In these tumors, as well as in 11 cases of leiomyomas, PCR-amplified DNA from the juxtamembrane (JM) domain of exon 11, the extracellular domain of exon 9 and the tyrosine kinase domain 1 of exon 13 showed a high frequency of c-kit mutation and was sequenced. RESULTS: Although c-kit mutations have previously been reported only in GISTs, we found c-kit mutations in the JM domain of exon 11 in one myogenic and one neurogenic tumor as well as in two GISTs. No c-kit mutation was seen in the 11 cases of leiomyomas. In addition, all four cases with c-kit mutation in exon 11 suffered a relapse sooner than the other cases without c-kit mutations. CONCLUSION: Clinically, the prognosis was worse for the patients with mutation-positive gastrointestinal mesenchymal tumors than for those with mutation-negative tumors. We therefore conclude that the gain-of-function mutation in exon 11 of the c-kit gene is an important prognostic factor for gastrointestinal mesenchymal tumors, including myogenic and neurogenic tumors as well as GISTs.

Evaluation of genetic heterogeneity in neuroblastoma.

BACKGROUND AND METHODS: The prognosis in neuroblastoma, which is the most common solid tumor in children, tends to vary greatly, and many studies have demonstrated both clinical and biological factors to be closely correlated with the outcome. In order to select the optimal treatment according to the degree of malignancy of neuroblastoma, it is essential to accurately and rapidly identify any genetic heterogeneity associated with the prognosis. We assessed the status of some genetic abnormalities (MYCN amplification, deletion of the short arm of chromosome 1, DNA ploidy, and a gain of the chromosome 17q region) associated with the prognosis using several molecular biological methods. RESULTS AND CONCLUSIONS: The combination of several molecular biological techniques is thus considered to be useful for elucidating the degree of malignancy of neuroblastoma. In particular, diagnostic analyses based on a combination of the fluorescence in situ hybridization (FISH) method and the quantitative polymerase chain reaction (PCR) method may be considered to be the most effective methods for quickly and accurately evaluating any aberrations in the gene dosages associated with the patients' outcomes.