Meningioma is the most common intracranial tumor, arising from arachnoid cells of the meninges. Monosomy 22 and inactivating mutations of NF2 are well-known genetic alterations of meningiomas. More recently, mutations in TRAF7, AKT1, KLF4, SMO, and PIK3CA were identified by next-generation sequencing. We here reviewed 553 meningiomas for the mutational patterns of the six genes. NF2 aberration was observed in 55 % of meningiomas. Mutations of TRAF7, AKT1, KLF4, PIK3CA, and SMO were identified in 20, 9, 9, 4.5, and 3 % of cases, respectively. Altogether, 80 % of cases harbored at least one of the genetic alterations in these genes. NF2 alterations and mutations of the other genes were mutually exclusive with a few exceptions. Clinicopathologically, tumors with mutations in TRAF7/AKT1 and SMO shared specific features: they were located in the anterior fossa, median middle fossa, or anterior calvarium, and most of them were meningothelial or transitional meningiomas. TRAF7/KLF4 type meningiomas showed different characteristics in that they occurred in the lateral middle fossa and median posterior fossa as well as anterior fossa and median middle fossa, and contained a secretory meningioma component. We also discuss the mutational hotspots of these genes and other genetic/cytogenetic alterations contributing to tumorigenesis or progression of meningiomas.
Recent genetic analyses using next-generation sequencers have revealed numerous genetic alterations in various tumors including meningioma, which is the most common primary brain tumor. However, their use as routine laboratory examinations in clinical applications for tumor genotyping is not cost effective. To establish a clinical sequencing system for meningioma and investigate the clinical significance of genotype, we retrospectively performed targeted amplicon sequencing on 103 meningiomas and evaluated the association with clinicopathological features. We designed amplicon-sequencing panels targeting eight genes including NF2 (neurofibromin 2), TRAF7, KLF4, AKT1, and SMO. Libraries prepared with genomic DNA extracted from PAXgenefixed paraffin-embedded tissues of 103 meningioma specimens were sequenced using the Illumina MiSeq. NF2 loss in some cases was also confirmed by interphase-fluorescent in situ hybridization. We identified NF2 loss and/or at least one mutation in NF2, TRAF7, KLF4, AKT1, and SMO in 81 out of 103 cases (79%) by targeted amplicon sequencing. On the basis of genetic status, we categorized meningiomas into three genotype groups: NF2 type, TRAKLS type harboring mutation in TRAF7, AKT1, KLF4, and/or SMO, and 'not otherwise classified' type. Genotype significantly correlated with tumor volume, tumor location, and magnetic resonance imaging findings such as adjacent bone change and heterogeneous gadolinium enhancement, as well as histopathological subtypes. In addition, multivariate analysis revealed that genotype was independently associated with risk of recurrence. In conclusion, we established a rapid clinical sequencing system that enables final confirmation of meningioma genotype within 7 days turnaround time. Our method will bring multiple benefits to neuropathologists and neurosurgeons for accurate diagnosis and appropriate postoperative management.
Pancreatic adenocarcinoma is a lethal disease that often develops a desmoplastic reaction in tumor stroma. In general, desmoplasia is thought to promote tumor growth. However, its molecular pathology and prognostic potential has not been fully investigated. Here we investigate 26 cases of pancreatic ductal adenocarcinoma, and examine the clinicopathological association between survival and expression levels of several molecular markers for stromal cells. These include alpha smooth muscle actin (SMA) and platelet-derived growth factor (PDGF) receptor β (PDGFRβ). Both are markers of activated fibroblasts or pancreatic stellate cells (PSCs) that play an important role in desmoplasia. The staining patterns of both molecular markers were not uniform so we categorized them into 3 grades (high, middle, and low) according to intensity. Interestingly, Kaplan-Meier analysis revealed that higher expression of PDGFRβ matched shorter prognosis (p = 0.0287, log-rank test) as well as lymphatic invasion and lymph node metastasis, whereas SMA did not (p = 0.6122).Our results suggest the prognostic potential of cancer stroma via PDGF-B signaling. Regulation of PDGF-B-associated signaling crosstalk between cancer cells and stroma cells, therefore, may indicate a possible therapeutic target for desmoplastic malignant tumors such as pancreatic adenocarcinoma.
Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a mesenchymal tumor that can affect virtually any region of the body. SFT/HPC of the thoracic cavity and soft tissue has been histologically considered a single biological entity termed SFT; in fact, NAB2-STAT6 gene fusion was recently identified in both diseases. In contrast, meningeal SFT and HPC still need to be investigated in detail with regard to gene fusion variants. The aim of this study was to verify the frequency of NAB2-STAT6 fusion and the relationship between fusion variants and clinicopathologic findings of SFT/HPC, especially meningeal SFT/HPC. We examined the NAB2-STAT6 fusion by reverse transcription polymerase chain reaction with 4 cases of meningeal SFT and 13 cases of meningeal HPC. NAB2-STAT6 fusion transcripts were identified in 12 of 17 cases, including NAB2ex6-STAT6ex17 (4/17, 24%), NAB2ex6-STAT6ex16 and NAB2ex4-STAT6ex2 (3/17, 18%, respectively), and NAB2ex5-STAT6ex16 (2/17, 12%). Three cases showed a pseudopapillary pattern, and 2 of them carried NAB2ex6-STAT6ex17. In addition, our meta-analysis revealed that the major fusion variant in meningeal SFT/HPC was NAB2ex6-STAT6ex16/17 (29/54, 54%), which was also common in soft tissue and intraperitoneum/retroperitoneum but rare in thoracic SFT. Fusion variant significantly correlated with age and histologic diagnosis in meningeal SFT/HPC but not with prognosis. Our results represented that meningeal SFT and HPC were in a single biological spectrum with NAB2-STAT6 gene fusion as was nonmeningeal SFT and further confirmed the organ-specific tumorigenic process and morphologic differences on the basis of fusion variants in meningeal SFT/HPC.
To our knowledge, this is the first report that demonstrates CD163 expression in meningioma not only by immunohistochemistry but also by reverse-transcription polymerase chain reaction, using primary culture cells, and provides the novel molecular function of CD163 to prevent apoptosis through the production of G-CSF in meningioma.
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