Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex
Mutated Genes and Abnormal Protein Expression (31)
Clicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.
|PTEN ||10q23.31 ||BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del || ||-PTEN and Glioblastoma || 443|
|DMBT1 ||10q26.13 ||GP340, muclin || ||-DMBT1 and Brain Tumours |
-DMBT1 and Glioblastoma
-DMBT1 and Brain Stem Glioma
-DMBT1 and Brain, Astrocytoma
|MMP2 ||16q12.2 ||CLG4, MONA, CLG4A, MMP-2, TBE-1, MMP-II || ||-MMP2 and CNS Tumors || 69|
|MGMT ||10q26 || || ||-MGMT and Oligodendroglioma || 56|
|KRIT1 ||7q21.2 ||CAM, CCM1 || ||-KRIT1 and Brain and CNS Tumours || 51|
|PDGFA ||7p22 ||PDGF1, PDGF-A || ||-PDGFA and Glioma || 36|
|MIR21 ||17q23.1 ||MIRN21, miR-21, miRNA21, hsa-mir-21 || ||-MicroRNA miR-21 and Brain Tumors || 33|
|NOTCH2 ||1p13-p11 ||hN2, AGS2, HJCYS || ||-NOTCH2 and Brain Tumours || 29|
|DONSON ||21q22.1 ||B17, C21orf60 || ||-DONSON and Brain and CNS Tumours || 25|
|GFAP ||17q21 ||ALXDRD || ||-GFAP and Oligodendroglioma || 23|
|CIC ||19q13.2 || || ||-CIC and Oligodendroglioma || 21|
|RTEL1 ||20q13.3 ||NHL, RTEL, DKCA4, DKCB5, PFBMFT3, C20orf41 || ||-RTEL1 and Brain and CNS Tumours || 20|
|CCM2 ||7p13 ||OSM, C7orf22, PP10187 || ||-CCM2 and Brain and CNS Tumours || 18|
|OLIG2 ||21q22.11 ||BHLHB1, OLIGO2, RACK17, PRKCBP2, bHLHe19 || ||-OLIG2 and Oligodendroglioma || 15|
|PDCD10 ||3q26.1 ||CCM3, TFAR15 || ||-PDCD10 and Brain and CNS Tumours || 15|
|S100A6 ||1q21 ||2A9, PRA, 5B10, CABP, CACY || ||-S100A6 Expression in CNS Tumors || 10|
|ROS1 ||6q22.1 ||ROS, MCF3, c-ros-1 || ||-ROS1 rearrangements in Glioblastoma || 9|
|RAF1 ||3p25 ||NS5, CRAF, Raf-1, c-Raf, CMD1NN || ||-RAF1 and Astrocytoma || 8|
|TGFB2 ||1q41 ||LDS4, TGF-beta2 || ||-TGFB2 and Brain Tumours || 6|
|ATRX ||Xq21.1 ||JMS, SHS, XH2, XNP, ATR2, SFM1, MRX52, RAD54, MRXHF1, RAD54L, ZNF-HX || ||-ATRX and Oligodendroglioma || 5|
|FAT1 ||4q35 ||FAT, ME5, CDHF7, CDHR8, hFat1 || ||-FAT1 and Glioblastoma || 4|
|NKX2-2 ||20p11.22 ||NKX2B, NKX2.2 || ||-NKX2-2 and Oligodendroglioma || 4|
|LRP5 ||11q13.2 ||HBM, LR3, OPS, EVR1, EVR4, LRP7, OPPG, BMND1, LRP-5, OPTA1, VBCH2 || ||-LRP5 and Brain and CNS Tumours || 4|
|CCDC26 ||8q24.21 ||RAM || ||-CCDC26 and Oligodendroglioma || 3|
|IQGAP1 ||15q26.1 ||SAR1, p195, HUMORFA01 || ||-IQGAP1 and Oligodendroglioma || 3|
|PTPRK ||6q22.2-q22.3 ||R-PTP-kappa || ||-PTPRK and Brain and CNS Tumours || 3|
|FTL ||19q13.33 ||LFTD, NBIA3 || ||-FTL and Oligodendroglioma || 1|
|LRRN2 ||1q32.1 ||GAC1, LRRN5, LRANK1, FIGLER7 || ||-LRRN2 and Oligodendroglioma || 1|
|CNTRL ||9q33.2 ||FAN, CEP1, CEP110, bA165P4.1 || ||-CNTRL and Oligodendroglioma || 1|
|GLTSCR2 ||19q13.3 ||PICT1, PICT-1 || ||-GLTSCR2 and Oligodendroglioma || 1|
|CLP1 ||11q12.1 ||HEAB, hClp1 || ||-CLP1 and Brain and CNS Tumours || 1|
Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).
Neill SG, Saxe DF, Rossi MR, et al.Genomic Analysis in the Practice of Surgical Neuropathology: The Emory Experience.
Arch Pathol Lab Med. 2017; 141(3):355-365 [PubMed
] Related Publications
The evaluation of central nervous system tumors increasingly relies on molecular genetic methods to aid in classification, offer prognostic information, and predict response to therapy. Available assays make it possible to assess genetic losses, amplifications, translocations, mutations, or the expression levels of specific gene transcripts or proteins. Current molecular diagnostics frequently use a panel-based approach and whole genome analysis, and generally rely either on DNA sequencing or on hybridization-based methodologies, such as those used in cytogenomic microarrays. In some cases, immunohistochemistry can be used as a surrogate for genetic analysis when the mutation of interest consistently results in overexpression or underexpression of a known protein product. In surgical neuropathology practice, the diagnostic workup of diffuse gliomas, medulloblastomas, low-grade circumscribed gliomas, as well as other diseases, now routinely incorporates the results of genomic studies. Here we summarize our institution's current approach to diagnostic surgical neuropathology, using these contemporary molecular diagnostic applications.
Sato R, Nakano T, Hosonaga M, et al.RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis.
Biomed Res Int. 2017; 2017:8032910 [PubMed
] Free Access to Full Article Related Publications
Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non-small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients.
Purpose. To determine if the MMP-9 genotype has an influence on development of pituitary adenoma (PA). Methodology. The study enrolled n = 86 patients with PA and n = 526 healthy controls (reference group). The genotyping of MMP-9 was carried out using the real-time polymerase chain reaction method. Results. Our data demonstrated that the MMP-9 (-1562) C/C genotype was more frequent in PA group than in healthy controls (81.4% versus 64.6%, p = 0.002); C/C genotype was more frequently present in PA females compared to healthy control females, 81.5% versus 64.6%, p = 0.018, as well. MMP-9 (-1562) C/C genotype was frequently observed for all subgroups: noninvasive and invasive, nonrecurrence, and inactive PA compared to healthy controls: 81.8% versus 64.6%, p = 0.021; 81.0% versus 64.6%, p = 0.041; 81.8% versus 64.6%, p = 0.005; 100.0% versus 64.6%, p < 0.001, respectively. MMP-9 (-1562) C/C genotype was more frequent in inactive PA compared to active PA: 100.0% versus 71.4%; p < 0.001. Conclusion. MMP-9 (-1562) C/C genotype plays a role in nonrecurrence, inactive, and invasive as well as in nonivasive PA development.
Understanding the mechanisms of glioblastoma at the molecular and structural level is not only interesting for basic science but also valuable for biotechnological application, such as the clinical treatment. In the present study, bioinformatics analysis was performed to reveal and identify the key genes of glioblastoma multiforme (GBM). The results obtained in the present study signified the importance of some genes, such as COL3A1, FN1, and MMP9, for glioblastoma. Based on the selected genes, a prediction model was built, which achieved 94.4% prediction accuracy. These findings might provide more insights into the genetic basis of glioblastoma.
RATIONAL: Cerebroretinal microangiopathy with calcifications and cysts (CRMCC) is believed to be an autosomal recessive genetic disease, with disorders in multisystem organs. Its characteristic neurological disorders manifested on neuroimaging are a triad of leukoencephalopathy, intracranial calcifications, and parenchymal cysts. In this paper, we report a CRMCC patient with multisystem involvement, focusing on the neuroimaging features, to get a better understanding of the rare disease and improve our diagnostic ability.
PATIENT CONCERNS: The 23-year-old female patient firstly presented with an adolescence onset of ophthalmological manifestations. Four years later, hematological and neurological disorders occurred, the latter of which demonstrated a relatively slow progression in the following 7 years preceding her presentation to our hospital.
INTERVENTIONS: During hospitalization, disorders involving digestive, cardiovascular and respiratory systems were also detected. In addition, a more comprehensive depiction of neurological disorders on neuroimaging was also obtained.
DIAGNOSES: On the basis of multiple system disorders and the detection of mutations in conserved telomere maintenance component 1(CTC1) gene, a diagnosis of CRMCC was made.
OUTCOMES: After supportive therapy during her 4-week hospitalization, the patient's general condition improved and was released from the hospital.
LESSONS: CRMCC could be primarily diagnosed with the aid of its multiple system disorders and remarkable neuroimaging features. Cerebral micro hemorrhages determined by the combination of CT and T2-weighted magnetic resonance images in our case could provide some additional information for diagnosis. Furthermore, several other associated disorders were depicted for the first time in our case, expanding the clinical spectrum of CRMCC.
He W, Huang L, Shen X, et al.Relationship between RSUME and HIF-1α/VEGF-A with invasion of pituitary adenoma.
Gene. 2017; 603:54-60 [PubMed
] Related Publications
The RWD-containing sumoylation enhancer (RSUME) can stabilize hypoxia-inducible factor-1α (HIF-1α) which promotes vascular endothelial growth factor-A (VEGF-A) expression. RSUME plays an important role in promoting the invasion of pituitary adenoma. In this study, we compared the mRNA and protein levels of RSUME, HIF-1α, and VEGF-A in pituitary adenoma tissue and analyzed the correlation. We found that the expression levels of RSUME, HIF-1α, and VEGF-A in invasive pituitary adenoma were significantly higher than in noninvasive pituitary adenoma. Moreover, a positive correlation was found between RSUME and HIF-1α/VEGF pathways. RSUME and HIF-1α were treated with hypoxia-mimicking CoCl2 and transfected into AtT-20 and GT1.1 cell lines to determine the relationship between them. It was found that RSUME effects post-transcriptional expression of HIF-1α regulated VEGF-A secretion. Reducing RSUME expression using siRNA transfection resulted in a decrease of the invasion inhibition rate of AtT-20 cells, as determined using Transwell and MTT assays. Together, we found that RSUME silencing can inhibit the invasion of pituitary adenoma cells.
Kramář F, Minárik M, Benešová L, et al.IDH1/2 Mutation and MGMT Promoter Methylation - the Relevant Survival Predictors in Czech Patients with Brain Gliomas.
Folia Biol (Praha). 2016; 62(5):194-202 [PubMed
] Related Publications
Gliomas are a heterogeneous group of tumours varying in prognosis, treatment approach, and overall survival. Recently, novel markers have been identified which are linked to patient prognosis and therapeutic response. Especially the mutation of the enzyme isocitrate dehydrogenase 1 or 2 (IDH1/2) gene and the O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status seem to be the most important predictors of survival. From 2012 to 2015, 94 Czech patients with primary brain tumours were enrolled into the study. The IDH1/2 mutation was detected by denaturing capillary electrophores.The methylation status of the MGMT gene and other 46 genes was revealed by MS-MLPA. In all 94 patients, the clinical data were correlated with molecular markers by Kaplan-Meier analyses and Cox regression model. The MGMT promoter methylation status was established and compared to clinical data. In our study eight different probes were used to elucidate the MGMT methylation status; hypermethylation was proclaimed if four and more probes were positive. This 3 : 5 ratio was tested and confirmed by Kaplan-Meier and Cox analyses. The study confirmed the importance of the IDH1/2 mutation and hypermethylation of the MGMT gene promoter being present in tumour tissue. Both markers are independent positive survival predictors; in the Cox model the IDH hazard ratio was 0.10 and in the case of MGMT methylation it reached 0.32. The methylation analysis of the panel of additional 46 genes did not reveal any other significant epigenetic markers; none of the candidate genes have been confirmed in the Cox regression analyses as an independent prognostic factor.
Han IB, Kim M, Lee SH, et al.Down-regulation of MicroRNA-126 in Glioblastoma and its Correlation with Patient Prognosis: A Pilot Study.
Anticancer Res. 2016; 36(12):6691-6697 [PubMed
] Related Publications
Glioblastoma is the most common primary malignant tumor of the adult human brain. Although microRNA-126 (miR-126) has been reported to exhibit expression abnormalities in various types of cancer, to date very few studies have examined changes in miR-126 level in glioblastoma. In this pilot study, we investigated the changes in miR-126 expression in newly-dissected primary glioblastoma to explore possible roles of miR-126 in patient prognosis. Total RNA was extracted from tumoral and adjacent non-cancerous tissues from 14 patients' paired frozen specimens. Using an established quantitative reverse transcriptase-PCR protocol, the levels of miR-126 in glioblastoma and adjacent non-tumor brain tissues were compared against small nucleolar RNA U48 (RNU48) as a reference gene. The expression of miR-126 in glioblastoma samples was significantly lower than in paired non-tumoral controls (p<0.05). Importantly, age-adjusted analyses suggest that glioblastoma patients with higher relative intratumoral miR-126 expression (i.e. 53-79% relative to that of the control tissue; n=7) had significantly improved survival duration than patients whose miR-126 levels were lower (i.e. 12-48%, n=7; stratified log-rank analysis p=0.011 when the dividing threshold was set at ≥51%; total: n=14, male: 8; female: 6). Thus, intraglioblastoma miR-126 may be down-regulated relative to normal tissue and patients with less down-regulation of intratumoral miR-126 expression could have improved postsurgical prognosis. Future clinical studies with larger sample sizes should be performed to validate this observation.
BACKGROUND: MicroRNAs are significantly involved in tumorigenesis and progression of glioma. However, the critical part they play in glioma have not been fully elaborated. miR-491 and Tripartite motif containing 28 (TRIM28) are reported to aberrantly express in glioblastoma multiforme (GBM). Here, we detected miR-491 and TRIM28 expression and function in glioma cells.
METHODS: We analyzed miR-491 expressions in 20 primary human GBM tissues and 6 control brain tissues by qRT-PCR assays and searched for The Cancer Genome Atlas (TCGA) database. Then we predicted possible mRNA target of miR-491 by TargetScan/MicroRNA and confirmed it via luciferase reporter assays. Knock-down of miR-491 and transfection of pLenti-TRIM28 were performed in U251 and U87 cells. Proliferation ability was examined by MTT and clone formation assays.
RESULTS: miR-491 expression was obviously reduced in GBM cells and tissues. There was a positive correlation between the down-regulation of miR-491 and poor prognosis. Spearman's correlation analysis demonstrated that miR-491 expression was negatively correlated with TRIM28 protein level. Possible mRNA binding sites of miR-491 predicted by TargetScan/MicroRNA were proved by luciferase assays. Clone formation and MTT assays indicated that up-regulation of miR-491 inhibited the proliferation of glioma cells.
CONCLUSIONS: miR-491 regulates glioma cells proliferation in vitro by targeting TRIM28.
Robinson LC, Santagata S, Hankinson TCPotential evolution of neurosurgical treatment paradigms for craniopharyngioma based on genomic and transcriptomic characteristics.
Neurosurg Focus. 2016; 41(6):E3 [PubMed
] Related Publications
The recent genomic and transcriptomic characterization of human craniopharyngiomas has provided important insights into the pathogenesis of these tumors and supports that these tumor types are distinct entities. Critically, the insights provided by these data offer the potential for the introduction of novel therapies and surgical treatment paradigms for these tumors, which are associated with high morbidity rates and morbid conditions. Mutations in the CTNNB1 gene are primary drivers of adamantinomatous craniopharyngioma (ACP) and lead to the accumulation of β-catenin protein in a subset of the nuclei within the neoplastic epithelium of these tumors. Dysregulation of epidermal growth factor receptor (EGFR) and of sonic hedgehog (SHH) signaling in ACP suggest that paracrine oncogenic mechanisms may underlie ACP growth and implicate these signaling pathways as potential targets for therapeutic intervention using directed therapies. Recent work shows that ACP cells have primary cilia, further supporting the potential importance of SHH signaling in the pathogenesis of these tumors. While further preclinical data are needed, directed therapies could defer, or replace, the need for radiation therapy and/or allow for less aggressive surgical interventions. Furthermore, the prospect for reliable control of cystic disease without the need for surgery now exists. Studies of papillary craniopharyngioma (PCP) are more clinically advanced than those for ACP. The vast majority of PCPs harbor the BRAF(v600e) mutation. There are now 2 reports of patients with PCP that had dramatic therapeutic responses to targeted agents. Ongoing clinical and research studies promise to not only advance our understanding of these challenging tumors but to offer new approaches for patient management.
Apps JR, Martinez-Barbera JPMolecular pathology of adamantinomatous craniopharyngioma: review and opportunities for practice.
Neurosurg Focus. 2016; 41(6):E4 [PubMed
] Related Publications
Since the first identification of CTNNB1 mutations in adamantinomatous craniopharyngioma (ACP), much has been learned about the molecular pathways and processes that are disrupted in ACP pathogenesis. To date this understanding has not translated into tangible patient benefit. The recent development of novel techniques and a range of preclinical models now provides an opportunity to begin to support treatment decisions and develop new therapeutics based on molecular pathology. In this review the authors summarize many of the key findings and pathways implicated in ACP pathogenesis and discuss the challenges that need to be tackled to translate these basic science findings for the benefit of patients.
BACKGROUND: Pituitary carcinoma (PC) is a rare type of malignant intracranial neoplasm defined as distant metastasis of pituitary adenoma (PA). Although PC incidence is low because only 0.1% to 0.2% of PAs ultimately develop into PCs, the prognosis is poor and 66% of patients die within the first year. Existing therapeutic measures, including surgical removal, chemotherapy, and radiotherapy, have limited effectiveness. The lack of efficacy of current treatments is largely caused by the limited understanding of the molecular pathogenesis of PA and the malignant transformation to PC. Therefore, the aim of this systematic review was to summarize published research regarding gene and protein expression in PC to clarify the molecular mechanisms underlying PC genesis and development and identify new candidate diagnostic biomarkers and therapeutic targets for potential use in personalized treatment of PC.
METHODS: We followed the PRISMA guidelines to plan and conduct this systematic review. PubMed, Embase, and Web of Science databases were searched for relevant studies conducted before December 16, 2015 describing the association of PC with gene expression at the mRNA and protein levels. MeSH terms combined with free terms were used to retrieve the references.
RESULTS: In total, 207 records were obtained by primary search, and 32 were included in the systematic review. Compared with normal pituitary gland and/or PA, 30 and 18 genes were found to have higher or lower expression, respectively, in PCs using different analytical methods. Among them, we selected 9 upregulated and 7 downregulated genes for further analysis based on their identification as candidate treatment targets in other cancers, potential clinical application, or further research value.
CONCLUSION: Previous studies demonstrated that many genes promote PC malignant transformation, angiogenesis, invasion, metastasis, and recurrence. Although most of these genes and proteins have not been fully analyzed with regard to their downstream mechanisms or potential diagnostic and therapeutic application, they have the potential to become candidate PC biomarkers and/or molecular targets for guiding personalized treatment. Modern advanced technologies should be utilized in future research to identify more candidate genes for PC pathogenesis, as precisely targeted gene therapies against PC are urgently required.
BACKGROUND: Diffuse gliomas, grades II and III, hereafter called lower-grade gliomas (LGG), have variable, difficult to predict clinical courses, resulting in multiple studies to identify prognostic biomarkers. The purpose of this study was to assess expression or methylation of the homeobox family gene SHOX2 as independent markers for LGG survival.
METHODS: We downloaded publically available glioma datasets for gene expression and methylation. The Cancer Genome Atlas (TCGA) (LGG, n=516) was used as a training set, and three other expression datasets (n=308) and three other methylation datasets (n=320), were used for validation. We performed Kaplan-Meier survival curves and univariate and multivariate Cox regression model analyses.
FINDINGS: SHOX2 expression and gene body methylation varied among LGG patients and highly significantly predicted poor overall survival. While they were tightly correlated, SHOX2 expression appeared more potent as a prognostic marker and was used for most further studies. The SHOX2 prognostic roles were maintained after analyses by histology subtypes or tumor grade. We found that the combination of SHOX2 expression and IDH genotype status identified a subset of LGG patients with IDH wild-type (IDHwt) and low SHOX2 expression with considerably favorable survival. We further investigated the combination of SHOX2 with other known clinically relevant markers of LGG (TERT expression, 1p/19q chromosome co-deletion, MGMT methylation, ATRX mutation and NES expression). When combined with SHOX2 expression, we identified subsets of LGG patients with significantly favorable survival outcomes, especially in the subgroup with worse prognosis for each individual marker. Finally, multivariate analysis demonstrated that SHOX2 was a potent independent survival marker.
INTERPRETATION: We have identified that SHOX2 expression or methylation are potent independent prognostic indicators for predicting LGG patient survival, and have potential to identify an important subset of LGG patients with IDHwt status with significantly better overall survival. The combination of IDH or other relevant markers with SHOX2 identified LGG subsets with significantly different survival outcomes, and further understanding of these subsets may benefit therapeutic target identification and therapy selections for glioma patients.
Wei Y, Sun J, Li XMicroRNA-215 enhances invasion and migration by targeting retinoblastoma tumor suppressor gene 1 in high-grade glioma.
Biotechnol Lett. 2017; 39(2):197-205 [PubMed
] Related Publications
OBJECTIVE: To elucidate the molecular mechanism of microRNA-215 (miR-215) in the migration and invasion of high grade glioma.
RESULTS: 42 Patients were analysed for clinicopathological characteristics. qRT-PCR showed that miR-215 was up-regulated in glioma tissues compared with non-neoplastic brain tissues (P < 0.05). The up-regulated miR-215 was closely associated with high grade glioma (P < 0.01) and poor overall survival (P < 0.01). Transwell assay showed that re-expression of miR-215 enhanced migration and invasion of glioma cells. miR-215 also down-regulated retinoblastoma tumor suppressor gene 1 (RB1) expression by targeting its 3'-UTR. Reversely, re-expression of RB1 inhibited partial effect of miR-215 on migration and invasion in vitro.
CONCLUSIONS: Re-expression of miR-215 promoted cell migration and invasion of glioma by targeting RB1. miR-215 can thus be used as a biomarker for tumor progression and prognosis in human high grade glioma.
BACKGROUND: Congenital intracranial tumors as a group are quite rare, representing only 0.5% to 1.5% of all pediatric brain neoplasms.
CASE REPORT: We reported a case of congenital mixed neuronal-glial tumor detected by ultrasound at 30 weeks of gestation. It showed that the tumor was 2.5 × 2.3 × 2.1 cm in size, located in the sellar region, regular shape, and slightly heterogeneous solid mass with a little cystic component. No color flow was present inside the tumor, but the peripheral encirclement by arterial circle of Willis. No other associated malformations were detected. Prenatal magnetic resonance imaging (MRI) which was taken subsequently confirmed the result of ultrasound and provided more detailed information such as fetal brain dysplasia.The fetal chromosomal karyotype analysis is normal. Single-nucleotide polymorphism (SNP)-based chromosomal microarray analysis (CMA) detected a 0.72-Mb duplication at 4q35.2 in fetus which was associated with epilepsy and cardiac anomalies. It also revealed a 0.13-Mb deletion at 6q26 located in PARK2 gene, and the mutation of the gene is known to be related to autosomal recessive juvenile Parkinson disease.The parents chose termination of pregnancy (TOP). The histological examination showed a mixed neuronal-glial tumor.
CONCLUSION: Prenatal detection of mixed neuronal-glial tumor is very rare. Ultrasound is of critical importance to detect the intracranial tumors, and MRI can give us some detailed information about the tumors. However, the precise histologic type was depended on the pathological examination. CMA should be necessary for the fetuses with congenital intracranial tumors, especially when the fetal chromosomal karyotype analysis is normal.
The revised WHO classification of tumors of the CNS 2016 has introduced the concept of the integrated diagnosis. The definition of medulloblastoma entities now requires a combination of the traditional histological information with additional molecular/genetic features. For definition of the histopathological component of the medulloblastoma diagnosis, the tumors should be assigned to one of the four entities classic, desmoplastic/nodular (DNMB), extensive nodular (MBEN), or large cell/anaplastic (LC/A) medulloblastoma. The genetically defined component comprises the four entities WNT-activated, SHH-activated and TP53 wildtype, SHH-activated and TP53 mutant, or non-WNT/non-SHH medulloblastoma. Robust and validated methods are available to allow a precise diagnosis of these medulloblastoma entities according to the updated WHO classification, and for differential diagnostic purposes. A combination of immunohistochemical markers including β-catenin, Yap1, p75-NGFR, Otx2, and p53, in combination with targeted sequencing and copy number assessment such as FISH analysis for MYC genes allows a precise assignment of patients for risk-adapted stratification. It also allows comparison to results of study cohorts in the past and provides a robust basis for further treatment refinement.
Li M, Li X, Xu S, et al.Protein phosphatase 4 catalytic subunit is overexpressed in glioma and promotes glioma cell proliferation and invasion.
Tumour Biol. 2016; 37(9):11893-11901 [PubMed
] Related Publications
Protein phosphatase 4 catalytic subunit (PP4C) has been identified to be overexpressed in various solid cancers. However, to date, the role of PP4C in glioma remains elusive. In the present study, we aimed to detect PP4C expression in glioma patients and explore its function in glioma and prognostic significance in patients with glioma. The expression levels of PP4C mRNA and protein in 30 glioma tissue specimens and 10 non-cancerous brain tissue specimens were detected by qRT-PCR and Western blot analysis. Moreover, immunohistochemistry was performed to assess PP4C expression in 120 glioma patients. The effects of siRNA-mediated PP4C silencing on the proliferation, migration, and invasion of U251 and U87 glioma cells were assessed. We found that PP4C was upregulated in glioma tissue at both mRNA and protein levels compared with non-cancerous brain tissue. Univariate and multivariate analyses indicated that high PP4C expression was an independent prognostic factor for poor survival of glioma patients. Knockdown of PP4C reduced the proliferation, migration, and invasion of U251 and U87 cells. In conclusion, our findings suggest that PP4C plays an oncogenic role in glioma development and progression and might serve as a prognostic biomarker as well as a potential therapeutic target for glioma.
Och W, Szmuda T, Sikorska B, et al.Recurrence-associated chromosomal anomalies in meningiomas: Single-institution study and a systematic review with meta-analysis.
Neurol Neurochir Pol. 2016 Nov - Dec; 50(6):439-448 [PubMed
] Related Publications
Complete removal of a meningioma (MG) does not guarantee relapse-free survival. Alterations on several chromosomes responsible for MG recurrence were suggested, although their role was not validated by a systematic review. Following the analysis of own 161 cases, all previously published data has been collected for evidence synthesis. Based on own series, WHO grade >I (odds ratio (OR)=92.0; 95%CI: 19.1-443.5) and a combination of loss of heterozygosity (LOH) on 1p and 14q (OR=10.2; 95%CI: 19-55.7) were the independent recurrence-specific prognosticators. The deleterious role of LOH on 1p/14q was demonstrated in a subset of parasagittal and falcine MGs. A total of 742 cases and 10 studies were pooled for the Individual Patient Data and Aggregate Data models of meta-analysis, respectively. The prognostic role of WHO classification (OR=90.4) and anomaly of chromosome 14 (OR=3.5) was confirmed. LOH on 14 showed lesser impact on recurrence than suggested by the WHO grading (area under the curve 0.65 for LOH vs. 0.74 for WHO). Fixed effect model of meta-analysis provided high summarized OR values for 1p (OR=5.4; 95%CI: 3.6-8.1) and 14q (OR=7.6; 95%CI: 4.3-13.6), and low for chromosome 22 (OR=1.6; 95%CI: 1.1-2.4). Final appraisal of recurrence-associated chromosomal alterations indicated that arms 1p and 14q deserve attention while predicting MG recurrence.
Chen S, Wang Y, Ni C, et al.HLF/miR-132/TTK axis regulates cell proliferation, metastasis and radiosensitivity of glioma cells.
Biomed Pharmacother. 2016; 83:898-904 [PubMed
] Related Publications
Glioma is a malignant cancer with high mortality. A key prognostic factor of glioma is radiosensitivity. It has also been known that microRNAs (miR) significantly contribute to the development of glioma. miR-132 has been previously reported to inhibit tumor growth in some cancers, but not well studied in glioma. It is necessary to understand the association between miR-132 and glioma, including miR-132 expression in glioma, effects of miR-132 on cancer metastasis and radiosensitivity, and the involved molecular mechanism. We first explored the expression levels of miR-132 in human normal and glioma tissues, then correlated the expression levels with different stages of glioma. Utilizing human glioma U87 cells, lentiviral transduction technique, luciferase reporter assay, wound healing assay, transwell invasion assay and clonogenic assay, we investigated the effects of hepatic leukemia factor (HLF), miR-132 and TTK protein kinase (TTK) on cancer cell viability, proliferation, migration, invasion and radiosensitivity. The expression of miR-132 was low in human glioma tissues, and the downregulated expression was associated with advanced glioma grades. HLF directly bound to the BS1 site of miR-132 promoter to enhance the expression of miR-132. HLF-mediated miR-132 was able to directly target and inhibit a downstream factor TTK, which had an oncogenic role. Overexpression of TTK could reverse the inhibitory effects of either miR-132 or HLF on cancer cell proliferation, metastasis and radioresistance. TTK acts as an oncogene in glioma. HLF-mediated miR-132 directly suppresses TTK expression, thus exerting inhibitory effects on cancer cell proliferation, metastasis and radioresistance.
Och W, Szmuda T, Kulbacki K, et al.The correlation of clinical and chromosomal alterations of benign meningiomas and their recurrences.
Neurol Neurochir Pol. 2016 Nov - Dec; 50(6):395-402 [PubMed
] Related Publications
Meningiomas (MGs) are the frequent benign intracranial tumors. Their complete removal does not always guarantee relapse-free survival. Recurrence-associated chromosomal anomalies in MGs haves been proposed as prognostic factors in addition to the World Health Organisation (WHO) grading, tumor size and resection rate. The aim of this study was to evaluate the frequency of deletions on chromosomes in sporadic MGs and to correlate them with the clinical findings and tumor behaviour. Along with survival, the tumor recurrence was the main endpoint. Chromosomal loss of heterozygosity (LOH) was studied. 46 benign MGs were subjected to the analysis, complete tumor resection was intended and no early mortalities were observed. Incomplete removal was related to parasagittal location and psammomatous hisptopathology (p<0.01). Chromosomal alterations were present in 82.6% of cases; LOH at 22q (67.4%) and 1p (34.8%) were the most frequent and associated with male sex (p=0.04). Molecular findings were not specific for any of the histopathologic grade. Tumor recurrence (14 of 46) correlated with tumor size (≥35mm), LOH at 1p, 14q, coexistence of LOH at 1p/14q, 10q/14q, 'complex karyotype' status (≥2 LOHs excluding 22q), patient age (younger <35), and Simpson grading of resection rate (≥3 of worse prognosis). The last 3 variables were independent significant prognostic factors in multivariate analysis and of the same importance in recurrence prediction (Receiver Operating Characteristic curves comparison p>0.05). Among the cases of recurrence, tumor progression was observed in 3 of 14. In 2 cases, LOH on 1p and/or coexistence of LOH 1p/14q correlated with anaplastic transformation.
Jiang N, Peng YP, Wang XY, et al.Assessing the association between EFEMP1 rs3791679 polymorphism and risk of glioma in a Chinese Han population.
Genet Mol Res. 2016; 15(3) [PubMed
] Related Publications
In this study, we assessed the association between the EFEMP1 rs3791679 polymorphism and glioma risk in a Chinese Han population. A total of 94 glioma patients and 206 healthy controls who conformed to the inclusion and exclusion criteria were recruited from Baogang Hospital between March 2012 and October 2014. The EFEMP1 rs3791679 gene polymorphism was assessed using a polymerase chain reaction-restriction fragment length polymorphism assay and the results were statistically analyzed using SPSS Statistics 17.0. The results of unconditional logistic regression analysis revealed that the GG genotype of EFEMP1 rs3791679 was positively correlated with increased susceptibility to glioma (adjusted OR = 2.09, 95%CI = 1.21-7.81). Moreover, the GG genotype of EFEMP1 rs3791679 was correlated with higher risk of glioma compared to the AA+GA genotype (OR = 2.60, 95%CI = 1.08-6.28) in the regressive model. In conclusion, we report that the EFEMP1 rs3791679 polymorphism influences glioma susceptibility in the Chinese Han population.
Fan SC, Zhou JG, Yin JZInvestigation of the role of XRCC1 genetic polymorphisms in the development of gliomas in a Chinese population.
Genet Mol Res. 2016; 15(3) [PubMed
] Related Publications
We conducted a study in a Chinese Han population to investigate the role of XRCC1 gene polymorphisms (Arg399Gln and Arg194Trp) with a risk of susceptibility to gliomas. Samples from 115 patients with gliomas and 228 control subjects were consecutively collected between March 2012 and December 2014. Genotype analysis of XRCC1 Arg399Gln and Arg194Trp was performed using polymerase chain reaction-restriction fragment length polymorphism assay. All the analyses were performed using the SPSS 17.0 software package. We observed that the XRCC1 Arg399Gln and Arg194Trp genotype frequencies conformed to the Hardy-Weinberg equilibrium. We observed that the Trp/Trp genotype of XRCC1 Arg194Trp was associated with an increased risk of glioma when compared to the wild-type genotype (odds ratio (OR) = 2.14, 95% confidence interval (CI) = 1.14-3.86, P = 0.03). In the dominant model, we found that the Arg/Trp + Trp/Trp genotype of XRCC1 Arg194Trp could significantly elevate the susceptibility of developing glioma (OR = 1.79, 95%CI = 1.07-0.94). However, we observed that the XRCC1 Arg399Gln genetic polymorphism did not influence the risk of glioma. In summary, we suggest that the XRCC1 Arg194Trp genetic polymorphism could be a predictive biomarker for the susceptibility to glioma in a Chinese population.
Fernández MB, Alonso VPConventional chemotherapy and perspectives for molecular-based oncological treatment in pediatric hemispheric low-grade gliomas.
Childs Nerv Syst. 2016; 32(10):1939-45 [PubMed
] Related Publications
INTRODUCTION: Pediatric low-grade gliomas (PLGG) are the most common primary central nervous system tumor in children. Patients in whom gross total resection can be achieved have an excellent overall (OS) and event-free survival (EFS) and do not require adjuvant therapy. However, children with unresectable tumors often experience multiple progressions and require additional treatment.
CONVENTIONAL CHEMOTHERAPY: Radiotherapy results in long-term tumor control, but it is associated with significant toxicity, making chemotherapy the preferred therapeutic option. Several chemotherapy combinations have been found to be successful in PLGG, but 5-year EFS has been below 60 % with most of them.
MOLECULAR-BASED TREATMENT: Recent molecular advances have led to a better understanding of the molecular pathways involved in the biology of LGG, allowing the development of promising tumor-specific, molecularly targeted therapies.
Bianchi F, Tamburrini G, Massimi L, Caldarelli MSupratentorial tumors typical of the infantile age: desmoplastic infantile ganglioglioma (DIG) and astrocytoma (DIA). A review.
Childs Nerv Syst. 2016; 32(10):1833-8 [PubMed
] Related Publications
OBJECT: Desmoplastic infantile gangliogliomas (DIGs) and desmoplastic infantile astrocytomas (DIAs) are tumors typical of the infantile age. A large size, with a mixed solid and cystic component, clinical presentation with progressing signs of increased intracranial pressure, a prominent benign desmoplastic structure at histological examination, and a favorable clinical course in the majority of cases are the prominent features of these tumors. The objective of the present paper was to review the pertinent literature on the topic together with our personal experience, with the aim of an updated review of the subject.
RESULTS AND CONCLUSIONS: Only 28 papers are present in the literature devoted to DIGs and DIAs, most of them reporting on single cases or small series, with a total of 107 patients aged from 5 days to 48 months with a slight male prevalence. Most of the reported cases refer to supratentorial and hemispheric locations, a few cases involving the hypothalamic region, the posterior fossa, and the spinal cord. The typical MRI appearance is of large mixed solid and cystic tumors with a spontaneous hyperintense T2 appearance of the solid part which also shows a strong contrast enhancement. Mixed ganglionic and astrocytic cells are identifiable in DIGs, whereas DIAs are typically featured by the exclusive presence of glial cells. In both cases, more primitive cells may be observed, which present a higher number of mitoses and these areas can mimic the features of malignant astrocytomas. Surgery represents the treatment of choice; however, radical removal has been reported as possible only in around 30 % of the cases: the low age of the patients together with their low weight and the large size of and the hyper-vascularized structure of the tumors represent the main factors limiting surgery. Pure observation is considered as first choice in children undergoing a partial/subtotal tumor resection, chemotherapic regimens being considered in cases of recurrences after a second look surgery. Long-term prognosis is favorable with mortality being related mostly to the rare midline (i.e., hypothalamic) locations, which beyond the functionally relevant site, tend to have an unusually more aggressive histological behavior.
Lassaletta A, Zapotocky M, Bouffet E, et al.An integrative molecular and genomic analysis of pediatric hemispheric low-grade gliomas: an update.
Childs Nerv Syst. 2016; 32(10):1789-97 [PubMed
] Related Publications
Hemispheric low-grade gliomas account for the second most common location in pediatric low-grade gliomas (PLGGs) after the cerebellum. The pathological spectrum includes gangliogliomas, dysembryoplastic neuroepithelial tumors (DNETs), diffuse astrocytomas, pilocytic astrocytomas, and pleomorphic xanthoastrocytomas (PXAs), among others. Clinically, hemispheric PLGGs represent a well-recognized cause of intractable epilepsy in children and adolescents. With an excellent long-term outcome, surgery remains the cornerstone and patients with gross total resection typically do not need any further therapies. The recent literature about hemispheric PLGGs was reviewed to provide an up-to-date overview of the molecular and cell biology of these tumors. Hemispheric PLGGs can harbor multiple alterations involving BRAFV600E, FGFR, NTRK, MYB/MYBL1, IDH, and BRAF-KIAA1549 fusions. However, the clinical significance of most of these alterations is still to be defined. The role of RAS/MAPK mutations and other alterations in hemispheric PLGGs is of interest from diagnostic, prognostic, and therapeutic perspectives. Molecular testing for these tumors should be encouraged, since the findings can have an important impact not only in prognosis but also in therapeutic strategies.
Lester A, Rapkins R, Nixdorf S, et al.Combining PARP inhibitors with radiation therapy for the treatment of glioblastoma: Is PTEN predictive of response?
Clin Transl Oncol. 2017; 19(3):273-278 [PubMed
] Related Publications
Glioblastoma (GBM) is fatal. The standard radiotherapy and chemotherapy (temozolomide) followed by an adjuvant phase of temozolomide provide patients with, on average, a 2.5 months benefit. New treatments that can improve sensitivity to the standard treatment are urgently needed. Herein, we review the mechanisms and utility of poly (ADP-ribose) polymerase inhibitors in combination with radiation therapy as a treatment option for GBM patients and the role of phosphatase and tensin homologue mutations as a biomarker of response.
Yuzawa S, Nishihara H, Tanaka SGenetic landscape of meningioma.
Brain Tumor Pathol. 2016; 33(4):237-247 [PubMed
] Related Publications
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.
Li Q, Jia H, Li H, et al.LncRNA and mRNA expression profiles of glioblastoma multiforme (GBM) reveal the potential roles of lncRNAs in GBM pathogenesis.
Tumour Biol. 2016; 37(11):14537-14552 [PubMed
] Related Publications
Glioblastoma multiforme (GBM) is the most common brain malignancy. Long non-coding RNAs (lncRNAs) are aberrantly expressed in many cancers and are involved in their cell proliferation, apoptosis, angiogenesis, and invasion. The functional roles of lncRNAs in GBM are less known. We analyzed a cohort of exon microarray datasets from The Cancer Genome Atlas. The differently expressed lncRNAs and mRNA were subjected to construct lncRNA-mRNA co-expression network. Probable functions for lncRNAs were predicted according to lncRNA-mRNA network and genomic adjacency by GO and pathway analysis. The expression of lncRNAs and mRNAs in GBM tissues versus normal brain tissues was examined by quantitative reverse transcription polymerase chain reaction. The 398 lncRNAs and 1995 mRNAs were identified as distinctively expressed in GBM. Probable functional roles for 98 lncRNAs were involved in 30 pathways and 32 gene functions related to tumorigenesis, development, and metastasis. The identified sets of key lncRNAs specific to GBM were subsequently verified by experiment in GBM tissues. Our reports predict the biological functions of a multitude of lncRNAs in GBM that could be potential diagnostic and prognostic biomarkers as well as therapeutic targets. Moreover, our research provides a road map for the identification and analysis of lncRNAs in tumors.
Aprile G, Casagrande M, De Maglio G, et al.Comparison of the molecular profile of brain metastases from colorectal cancer and corresponding primary tumors.
Future Oncol. 2017; 13(2):135-144 [PubMed
] Related Publications
AIM: Little is known about molecular biology of brain metastasis (BM) from colorectal cancer and its concordance with matched primary tumors.
MATERIALS & METHODS: We identified 56 consecutive colorectal cancer patients who underwent neurosurgical resection of BM. Tumor samples were tested for KRAS, NRAS, BRAF and PIK3CA. The molecular profile of the brain lesion was compared with the corresponding primary tumor.
RESULTS: The molecular profile concordance rate was 95.1%. Median survival after neurosurgery was 5.5 months (95% CI: 4.7-6.3); median overall survival was 24.0 months (95% CI: 15.6-32.4).
CONCLUSION: In this cohort, we report a high frequency of KRAS mutations and a very high concordance rate between the molecular status of BM and that of matched primary tumors.
Glioblastoma multiforme (GBM) is the most common malignant brain tumor. This study aimed to identify the hub genes and regulatory factors of GBM subgroups by RNA sequencing (RNA-seq) data analysis, in order to explore the possible mechanisms responsbile for the progression of GBM. The dataset RNASeqV2 was downloaded by TCGA-Assembler, containing 169 GBM and 5 normal samples. Gene expression was calculated by the reads per kilobase per million reads measurement, and nor malized with tag count comparison. Following subgroup classification by the non-negative matrix factorization, the differentially expressed genes (DEGs) were screened in 4 GBM subgroups using the method of significance analysis of microarrays. Functional enrichment analysis was performed by DAVID, and the protein-protein interaction (PPI) network was constructed based on the HPRD database. The subgroup-related microRNAs (miRNAs or miRs), transcription factors (TFs) and small molecule drugs were predicted with pre-defined criteria. A cohort of 19,515 DEGs between the GBM and control samples was screened, which were predominantly enriched in cell cycle- and immunoreaction-related pathways. In the PPI network, lymphocyte cytosolic protein 2 (LCP2), breast cancer 1 (BRCA1), specificity protein 1 (Sp1) and chromodomain-helicase-DNA-binding protein 3 (CHD3) were the hub nodes in subgroups 1-4, respectively. Paired box 5 (PAX5), adipocyte protein 2 (aP2), E2F transcription factor 1 (E2F1) and cAMP-response element-binding protein-1 (CREB1) were the specific TFs in subgroups 1-4, respectively. miR‑147b, miR‑770-5p, miR‑220a and miR‑1247 were the particular miRNAs in subgroups 1-4, respectively. Natalizumab was the predicted small molecule drug in subgroup 2. In conclusion, the molecular regulatory mechanisms of GBM pathogenesis were distinct in the different subgroups. Several crucial genes, TFs, miRNAs and small molecules in the different GBM subgroups were identified, which may be used as potential markers. However, further experimental validations may be required.