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Identifying molecular features is an essential component of the management and targeted therapy of brain metastases (BMs). The molecular features are different between primary lung cancers and BMs of lung cancer. Here we report the DNA and RNA mutational profiles of 43 pathological samples of BMs. In addition to previously reported mutational events associated with targeted therapy, PTPRZ1-MET, which was previously exclusively identified in glioma, was present in two cases of BMs of lung cancer. Furthermore, MET exon 14 skipping may be more common (6/37 cases) in BMs of lung cancer than the frequency previously reported in lung cancer. These findings highlight the clinical significance of targeted DNA plus RNA sequencing for BMs and suggest PTPRZ1-MET and MET exon 14 skipping as critical molecular events that may serve as targets of targeted therapy in BMs.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/secundario , Fusión de Oncogenes , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/genética , Adulto , Anciano , Neoplasias Encefálicas/metabolismo , Exones , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/metabolismoRESUMEN
Tumor microenvironment (TME) is a complex and dynamic evolving environment which facilitates tumor proliferation and progression. We aimed at investigating the characteristics of tumor microenvironment and its prognostic value in gliomas. Transcriptome data of 702 glioma samples from The Cancer Genome Atlas were included as training dataset, while 325 samples from Chinese Glioma Genome Atlas database and 268 samples from GSE16011 database were used to validate. We found that the infiltration of stromal and immune cell varied in gliomas of different grades and pathological types, and was associated with poor prognosis. Based on the gene expression profile, we constructed a TME-related signature (TMERS), which was closely related to clinical features and genomic variation of gliomas. In TMERS-high group, specific gene mutations and increased copy number alternations were observed. Kaplan-Meier survival and Cox regression analysis showed that TMERS was an independent prognostic indicator. Then we developed a nomogram prognostic model to predict 1-year, 3-year and 5-year survival of patients. Functional analysis confirmed that TMERS could reflect the status of glioma microenvironment, and immunological analysis showed that macrophages were significantly enriched in the TMERS-high group. We established a novel TME-related signature for predicting prognosis and provided new insights into immunotherapy.
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Glioma , Microambiente Tumoral , Glioma/patología , Humanos , Inmunoterapia , Pronóstico , Transcriptoma , Microambiente Tumoral/genéticaRESUMEN
AIM: No comprehensive and objective methods yet exist for predicting postoperative seizure. PATIENTS & METHODS: mRNA-seq data and corresponding postoperative seizure status of 109 low-grade glioma samples were obtained from Chinese Glioma Genome Atlas database and divided into two sets randomly. Logistic regression and receiver operating characteristic analysis with risk score method were used to develop a ten-gene prediction model. RESULTS: Considering gene number and area under the curve of receiver operating characteristic, a ten-gene model was generated which showed an area under the curve of 0.9965 in training set. Patients with high-risk scores had higher probability of postoperative seizure compared with those with low-risk scores. CONCLUSION: This is the first prediction model for postoperative seizures in gliomas, integrating multiple genes. Clinical application may help patients with postoperative seizure control.
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Biomarcadores de Tumor , Neoplasias Encefálicas/complicaciones , Neoplasias Encefálicas/genética , Glioma/complicaciones , Glioma/genética , Complicaciones Posoperatorias , ARN Mensajero , Convulsiones/diagnóstico , Convulsiones/etiología , Adulto , Anciano , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica/métodos , Glioma/patología , Glioma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Pronóstico , Curva ROC , Resultado del Tratamiento , Adulto JovenRESUMEN
Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs.
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Neoplasias Encefálicas/genética , Glioblastoma/genética , Glioma/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/genética , Adolescente , Adulto , Anciano , Antineoplásicos Alquilantes , Western Blotting , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/secundario , Línea Celular Tumoral , Quimioradioterapia , Dacarbazina/análogos & derivados , Dacarbazina/uso terapéutico , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/secundario , Glioma/patología , Glioma/terapia , Células HEK293 , Humanos , Intrones/genética , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ARN , Temozolomida , Translocación Genética , Adulto JovenRESUMEN
Aspergillosis of the central nervous system is a rare fungal infection that is mainly reported in patients with immune deficiency, such as AIDS patients and organ transplant patients treated with immunosuppressive agents, and is uncommon among patients with intact immune function. We report here a rare case of intracranial aspergillosis in a patient who had previously undergone a parietal lobe tumorectomy. Aspergillus fumigatus was confirmed by histopathology, and susceptibility tests reported that this infection should respond to voriconazole. We believe the immunosuppression resulting from surgical trauma and glucocorticosteroid treatment may be contributing to the infection, and therefore management of these two factors may improve the prognosis.
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Aspergilosis/microbiología , Aspergillus fumigatus/aislamiento & purificación , Absceso Encefálico/microbiología , Neoplasias Encefálicas/cirugía , Lóbulo Parietal/cirugía , Complicaciones Posoperatorias , Adulto , Antifúngicos/uso terapéutico , Aspergilosis/tratamiento farmacológico , Absceso Encefálico/tratamiento farmacológico , Neoplasias Encefálicas/patología , Humanos , Inmunocompetencia , Masculino , Pruebas de Sensibilidad Microbiana , Lóbulo Parietal/patología , Pronóstico , Voriconazol/uso terapéuticoRESUMEN
OBJECTIVE: To employ whole-genome messenger RNA profiling to identify the genes involved in malignant progression in glioma. METHODS: The whole genome expressed genes were profiled in 220 glioma patients from the Chinese Glioma Genome Atlas (97 LGGs and 123 HGGs). The differential expressed genes between LGG and HGG were identified by SAM analysis. Microarray data were validated by immunohistochemistry. RESULTS: Among all the detected genes, the genes up-regulated mostly in high-grade glioma were IGFBP-2, CKLF, PTTG1, OSTCL and PTTG2 while those down-regulated mostly SEC31, RRP7B, HOOK3, SNRPN and CSMD3. Validation of IGFBP-2 with immunohistochemical staining showed a good correlation with the microarray data. CONCLUSION: A panel of potential genes of malignant transformation may serve as future targets of gene therapy for glioma.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Glioma/genética , Glioma/patología , Perfilación de la Expresión Génica , Genes Relacionados con las Neoplasias , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , ARN Mensajero/genéticaRESUMEN
Tumor recurrence is a common clinical dilemma in diffuse gliomas. We aimed to identify a recurrence-related signature to predict the prognosis for glioma patients. In the public Chinese Glioma Genome Atlas dataset, we enrolled multi-omics data including genome, epigenome and transcriptome across primary and recurrent gliomas. We included RNA sequencing data from the batch 1 patients (325 patients) as the training set, while RNA sequencing data from the batch 2 patients (693 patients) were selected as the validation set. The R language was used for subsequent analysis. Compared with primary gliomas, more somatic mutations and copy number alterations were revealed in recurrent gliomas. In recurrent gliomas, we identified 113 genes whose methylation levels were significantly different from those of the primary glioma. Through differential expression analysis between primary and recurrent gliomas, we screened 121 recurrence-related genes. Based on these 121 gene expression profiles, consensus clustering of 325 patients yielded two robust groups with different molecular and prognostic features. We developed a recurrence-related risk signature with the lasso regression algorithm. High-risk group had shorter survival and earlier tumor recurrence than the low-risk group. Compared with traditional indicators, the signature showed better prognostic value. In addition, we constructed a nomogram model to predict glioma survival. Functional characteristics analysis found that the signature was associated with cell division and cell cycle. Immune analysis suggested that immunosuppressive status and macrophages might promote glioma recurrence. We demonstrated a novel 18-gene signature that could effectively predict recurrence and prognosis for glioma patients.
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In glioma, kinesin family member 23 (KIF23) is up-regulated and plays a vital role in oncogenesis. However, the mechanism underlying KIF23 overexpression in malignant glioma remains to be elucidated. This study aims to find potential causes of KIF23 high expression at genome level. To clarify this issue, we obtained point mutation and copy number alterations (CNAs) of KIF23 in 319 gliomas using whole-exome sequencing. Only two glioma samples with missense mutations in KIF23 coding region were identified, while 7 patients were detected with amplification of KIF23. Additional analysis showed that KIF23 amplification was significantly associated with higher expression of KIF23. Gene ontology analysis indicated that higher copy number of KIF23 was associated TNF-α signaling pathway and mitotic cell circle checkpoint, which probably caused by subsequent upregulated expression of KIF23. Moreover, pan-cancer analysis showed that gaining of copy number was significantly associated with higher expression of KIF23, consolidating our findings in glioma. Thus, it was deduced that elevated KIF23 expression in glioma tended to be caused by DNA copy number amplification, instead of mutation.
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BACKGROUND: Dysregulated receptor tyrosine kinases, such as the mesenchymal-epidermal transition factor (MET), have pivotal role in gliomas. MET and its interaction with the tumor microenvironment have been previously implicated in secondary gliomas. However, the contribution of MET gene to tumor cells' ability to escape immunosurveillance checkpoints in primary gliomas, especially in glioblastoma (GBM), which is a WHO grade 4 glioma with the worst overall survival, is still poorly understood. METHODS: We investigated the relationship between MET expression and glioma microenvironment by using multiomics data and aimed to understand the potential implications of MET in clinical practice through survival analysis. RNA expression data from a total of 1243 primary glioma samples (WHO grades 2-4) were assembled, incorporating The Cancer Genome Atlas, Chinese Glioma Genome Atlas, and GSE16011 data sets. RESULTS: Pearson's correlation test from the three data sets indicated that MET showed a robust correlation with programmed death-ligand 1 (PD-L1) and STAT pathways. Western blot analysis revealed that in GBM cell lines (N33 and LN229), PD-L1 and phosphorylated STAT4 were upregulated by MET activation treatment with hepatocyte growth factor and were downregulated on MET suppression by PLB-1001. Tumor tissue microarray analysis indicated a positive correlation between MET and PD-L1 and macrophage-associated markers. Chromatin immunoprecipitation-PCR assay showed enrichment of STAT4 in the PD-L1 DNA. Transwell co-culture and chemotaxis assays revealed that knockdown of MET in GBM cells inhibited macrophage chemotaxis. Moreover, we performed CIBERSORTx and single-cell RNA sequencing data analysis which revealed an elevated number of macrophages in glioma samples with MET overexpression. Kaplan-Meier survival analysis indicated that activation of the MET/STAT4/PD-L1 pathway and upregulation of macrophages were associated with shorter survival time in patients with primary GBM. CONCLUSIONS: These data indicated that the MET-STAT4-PD-L1 axis and tumor-associated macrophages might enforce glioma immune evasion and were associated with poor prognosis in GBM samples, suggesting potential clinical strategies for targeted therapy combined with immunotherapy in patients with primary GBM.
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Antígeno B7-H1/metabolismo , Neoplasias Encefálicas/inmunología , Glioblastoma/inmunología , Macrófagos/inmunología , Proteínas Proto-Oncogénicas c-met/metabolismo , Factor de Transcripción STAT4/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Femenino , Glioblastoma/genética , Glioblastoma/metabolismo , Humanos , Macrófagos/metabolismo , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Proto-Oncogénicas c-met/inmunología , Factor de Transcripción STAT4/genética , Factor de Transcripción STAT4/inmunología , Transducción de Señal/inmunología , Escape del TumorRESUMEN
PURPOSE: Incidentally discovered diffusely infiltrating lower-grade gliomas (incidental LGGs, iLGGs) are defined as gliomas occasionally found in patients without tumor-related symptoms. At present, very few in-depth research studies on incidental LGGs were reported. We aimed to find out the inherent difference between iLGGs and LGGs with tumor-related symptoms. PATIENTS AND METHODS: We enrolled 2486 all-grade gliomas and screened 1594 lower-grade gliomas for further analysis. Medical records were retrospectively reviewed for iLGGs. Clinical and mRNA sequencing data were collected for in-depth analysis. RESULTS: We found that with increasing grade, the proportion of incidental glioma patients decreased obviously. In 1594 patients who underwent craniotomy for LGG, 80 (5%) patients were discovered incidentally. Grade II patients (88%) and patients bearing 1p/19q co-deletion in their tumors (23%) were more likely to be diagnosed as iLGGs. Regular radiological screening (48%) and trauma (24%) were the main complaint for brain imaging for iLGGs. Kaplan-Meier survival analysis indicated that iLGGs patients lived a significantly longer survival and Cox regression analysis revealed that iLGGs were an independent indicator of better prognosis. Subsequent gene set enrichment analysis and differential expression analysis based on the gene expression profile revealed that mitochondrial aerobic respiration process was enriched in iLGGs. Moreover, we found that iLGGs tended to generate energy by unique mitochondrial aerobic respiration. CONCLUSION: These results provided a primitive exploration of iLGGs, which may potentially assist clinical neurosurgeons with personalized management of iLGGs.
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Gliomas are the most common type of primary brain tumor in adults with a high mortality rate. Low-grade gliomas progress to glioblastoma multiforme (GBM) in the majority of cases, forming secondary GBM (sGBM), followed by rapid fatal clinical outcomes. Protein tyrosine phosphatase receptor type Z1 (PTPRZ1)-MET proto-oncogene receptor tyrosine kinase (MET) (ZM) fusion has been identified as a biomarker for sGBM that is involved in glioma progression, but the mechanism of gliomagenesis and pathology of ZM-negative sGBM has remained to be fully elucidated. A whole-transcriptome signature is thus required to improve the outcome prediction for patients with sGBM without ZM fusion. In the present study, whole-transcriptome sequencing on 42 sGBM samples with or without ZM fusion from the Chinese Glioma Genome Atlas database identified mRNAs with differential expression between patients with and without ZM fusion and the most significant survival-associated genes were identified. A 6-gene signature was identified as a novel prognostic model reflecting survival probability in patients with ZM-negative sGBM. Clinical characteristics in patients with a high or low risk score value were analyzed with the Kaplan-Meier method and a two-sided log-rank test. In addition, ZM-negative sGBM patients with a high risk score exhibited an increase in immune cells, NF-κB-induced pathway activation and a decrease in endothelial cells compared with those with a low risk score. The present study demonstrated the potential use of a next-generation sequencing-based cancer gene signature in patients with ZM-negative sGBM, indicating possible clinical therapeutic strategies for further treatment of such patients.
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PURPOSE: Autophagy plays a vital role in cancer initiation, malignant progression, and resistance to treatment; however, autophagy-related gene sets have rarely been analyzed in glioblastoma. The purpose of this study was to evaluate the prognostic significance of autophagy-related genes in patients with glioblastoma. PATIENTS AND METHODS: Here, we collected whole transcriptome expression data from the Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA) datasets to explore the relationship between autophagy-related gene expression and glioblastoma prognosis. R language was the primary analysis and drawing tool. RESULTS: We screened 531 autophagy-related genes and identified 14 associated with overall survival in data from 986 patients with glioblastoma. Patients could be clustered into two groups (high and low risk) using expression data from the 14 associated genes, based on significant differences in clinicopathology and prognosis. Next, we constructed a signature based on the 14 genes and found that most patients designated high risk using our gene signature were IDH wild-type, MGMT promoter non-methylated, and likely to have more malignant tumor subtypes (including classical and mesenchymal subtypes). Survival analysis indicated that patients in the high-risk group had dramatically shorter overall survival compared with their low-risk counterparts. Cox regression analysis further confirmed the independent prognostic value of our 14 gene signature. Moreover, functional and ESTIMATE analyses revealed enrichment of immune and inflammatory responses in the high-risk group. CONCLUSION: In this study, we identified a novel autophagy-related signature for the prediction of prognosis in patients with glioblastoma.
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Background: Immunotherapy provided unprecedented advances in the treatment of several previously untreated cancers. However, these immunomodulatory maneuvers showed limited response to patients with glioma in clinical trials. Our aim was to depict the immune characteristics of glioma with immune cytolytic activity at genetic and transcriptome levels. Methods: In total, 325 gliomas from CGGA dataset as training cohort and 699 gliomas from TCGA dataset as validation cohort were enrolled in our analysis. We calculated the immune cytolytic activity for 1,000 of gliomas. The characteristics of immune cytolytic activity in gliomas were interpreted by the corresponding clinical, molecular genetics and radiological information. Results: We found that immune cytolytic activity was highly associated with molecular, clinical, and edema extent. High cytolytic activity gliomas were more likely to be diagnosed as glioblastoma and might be a potential marker of mesenchymal subtype. Moreover, those gliomas exhibited significantly increased copy number alterations including recurrent focal amplifications of PDGFA and EGFR, as well as recurrent deletions of CDKN2A/B. Subsequent biological function analysis revealed that the immune response and immune checkpoints expression were significantly correlated with the cytolytic activity of gliomas. Immune cytolytic activity was significantly positively associated with the extent of peri-tumor edema and was independently correlated with reduced survival time. Conclusion: Our results highlighted the immunoregulatory mechanism heterogeneity of gliomas. Cytolytic activity, indirectly reflected by the extent of peri-tumor edema, may provide a potential index to evaluate the status of immune microenvironment and immune checkpoints in glioma, which should be fully valued for precision classification and immunotherapy.
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Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Citotoxicidad Inmunológica/genética , Citotoxicidad Inmunológica/inmunología , Glioma/genética , Glioma/inmunología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Variaciones en el Número de Copia de ADN/genética , Variaciones en el Número de Copia de ADN/inmunología , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/inmunología , Glioblastoma/genética , Glioblastoma/inmunología , Humanos , Inmunoterapia/métodos , Estudios Retrospectivos , Transcriptoma/genética , Transcriptoma/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Background: Gliomas are aggressive tumors with various molecular and clinical characteristics and exhibit strongly resistance to radio-chemotherapy. Programmed cell death 1 ligand 2 (PD-L2) is a cell surface protein, which was reported in many cancers, modulating cancer-associated immune responses, while the role of PD-L2 in gliomas remained unclear. Herein, we aimed to investigate the biological behaviors and clinical prognostic values of PD-L2 in gliomas. Methods: Totally, we enrolled RNA sequencing data of 325 glioma samples from Chinese Glioma Genome Atlas (CGGA) as training cohort and RNA expression data of 1032 samples from The Cancer Genome Atlas (TCGA) dataset as validation cohort in this research. Then, the clinical and molecular characteristics, and the prognostic value of PD-L2 were analyzed. Results: We found that PD-L2 expression level was significantly upregulated in higher grade glioma and IDH wild-type glioma. Receiver Operating Characteristic (ROC) analysis revealed that PD-L2 was a potential indicator of mesenchymal subtype. PD-L2 exhibited tight relationship with immune response and immune-modulating process in glioma. Moreover, PD-L2 expression level could predict unfavorable prognoses of patients independent of age, grade, IDH status and 1p/19q status. Conclusions: Our study revealed that PD-L2 was closely related with inflammation and immune response. Patients with lower PD-L2 expression level tended to experience improved survival. Targeting PD-L2 may become a valuable approach for the treatment of gliomas in clinical practice.
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The impact of sexual dysfunction (SD) is distressing to many male patients with pituitary adenomas which affect both physical and psychological health. The research explored to identify risk factors affecting sexual function and the prognosis of male patients with pituitary adenomas. Two hundred and fifty-four male patients, who aged between 18 and 60 (mean ± s.d.: 44.16 ± 10.14) years and diagnosed with pituitary adenomas, were retrospectively analyzed. One hundred and fifty-nine patients (62.6%) complained of SD prior to surgery. The mean International Index of Erectile Function (IIEF-5) in patients with giant adenomas was 16.13 ± 2.51, much smaller than those with microadenomas or macroadenomas (P < 0.05). All the patients showed significant improvement in terms of erectile dysfunction (ED) following surgery (P < 0.05). In addition, complete resection achieved a higher degree of SD relief than partial resection. The incidence of SD in functioning pituitary adenomas (FPAs) was much higher than that in nonfunctioning pituitary adenomas (NFPAs) (P < 0.05). In addition, compared with NFPAs, males with prolactinomas (82.8%) had the higher prevalence of SD and significantly improvement following surgical intervention (P < 0.05). An inverse relationship was identified between decreasing testosterone levels and increasing incidence of SD before surgery (P < 0.05). There was no significant difference between 6 months and 12 months after surgery in serum testosterone level (P > 0.05). Our results indicated that surgical therapy could be optimized for improvements in SD and that testosterone levels can be used as a sensitive indicator to predict the recovery rate of sexual function in patients with pituitary adenomas following surgery and the serum testosterone level will stay stable in 6 months after surgery.
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Adenoma/complicaciones , Neoplasias Hipofisarias/complicaciones , Disfunciones Sexuales Fisiológicas/etiología , Adenoma/patología , Adenoma/cirugía , Adolescente , Adulto , Estudios de Cohortes , Disfunción Eréctil/epidemiología , Disfunción Eréctil/etiología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Análisis Multivariante , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/cirugía , Valor Predictivo de las Pruebas , Pronóstico , Prolactinoma/complicaciones , Prolactinoma/cirugía , Estudios Retrospectivos , Factores de Riesgo , Disfunciones Sexuales Fisiológicas/epidemiología , Testosterona/sangre , Resultado del Tratamiento , Adulto JovenRESUMEN
AIMS: To explore the prognostic and clinicopathological features of glioma with Paxillin (PXN) expression based on a large number of samples. METHODS: RNA sequencing data of 325 glioma samples from Chinese Glioma Genome Atlas (CGGA) database were obtained as discovery set. Three additional datasets were further obtained as validation sets. The protein expression pattern of PXN in glioma was measured by IHC. Kaplan-Meier survival and multivariate Cox analysis were used to estimate the survival distributions. Moreover, the functional annotation of PXN was also analyzed. RESULTS: In the discovery set, PXN overexpression was significantly associated with high-grade glioma as well as the higher mortality in survival analysis (log-rank test, P < 0.01). The results of the other validation datasets showed similar findings. PXN also served as an independent prognostic biomarker in glioblastoma patients. Functional assays showed that PXN contributed to glioma cell proliferation and invasion. CONCLUSION: PXN plays as an oncogene in glioma progression and suggests a new potential biotarget for therapy.
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Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/mortalidad , Glioblastoma/metabolismo , Glioblastoma/mortalidad , Paxillin/metabolismo , Adulto , Anciano , Apoptosis/fisiología , Línea Celular Tumoral , Proliferación Celular , Bases de Datos de Ácidos Nucleicos , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Paxillin/genética , ARN Mensajero/metabolismo , ARN Interferente Pequeño/farmacologíaRESUMEN
The World Health Organization (WHO) grading of gliomas stratifies tumors by histology. However, the aggressiveness of tumors in each grade still shows great heterogeneity. Phosphohistone H3 (pHH3) has been reported as an accurate marker of cells within the mitotic phase of the cell cycle in many kinds of cancers. To evaluate the role of pHH3 in predicting patient outcome and to annotate the functions of pHH3 in WHO grade II-IV gliomas, we analyzed the expression pattern of pHH3 and pHH3 associated genes by IHC and mRNA expression profiling. Phosphohistone H3, mRNA enrichment of histone H3 and associated gene signature all showed prognostic value in adult diffuse gliomas. Gene set enrichment analysis suggested that the expression of pHH3 had positive correlation with both epithelial to mesenchymal transition and immune response. These findings suggest that subgroups of diffuse gliomas defined by pHH3 and pHH3 signatures possess distinctive prognostic and biological characteristics.
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Biomarcadores de Tumor/análisis , Neoplasias Encefálicas/patología , Transición Epitelial-Mesenquimal , Glioma/patología , Histonas/biosíntesis , Adulto , Anciano , Neoplasias Encefálicas/mortalidad , Femenino , Perfilación de la Expresión Génica , Glioma/mortalidad , Histonas/análisis , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Fosforilación , Pronóstico , Modelos de Riesgos Proporcionales , TranscriptomaRESUMEN
Anaplastic gliomas are characterized by variable clinical and genetic features, but there are few studies focusing on the substratification of anaplastic gliomas. To identify a more objective and applicable classification of anaplastic gliomas, we analyzed whole genome mRNA expression profiling of four independent datasets. Univariate Cox regression, linear risk score formula and receiver operating characteristic (ROC) curve were applied to derive a gene signature with best prognostic performance. The corresponding clinical and molecular information were further analyzed for interpretation of the different prognosis and the independence of the signature. Gene ontology (GO), Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA) were performed for functional annotation of the differences. We found a three-gene signature, by applying which, the anaplastic gliomas could be divided into low risk and high risk groups. The two groups showed a high concordance with grade II and grade IV gliomas, respectively. The high risk group was more aggressive and complex. The three-gene signature showed diagnostic and prognostic value in anaplastic gliomas.
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Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/genética , Glioma/diagnóstico , Glioma/genética , ARN Mensajero/metabolismo , Adulto , Perfilación de la Expresión Génica , Humanos , Persona de Mediana Edad , Pronóstico , ARN Mensajero/biosíntesis , ARN Mensajero/genéticaRESUMEN
PTPRZ1-MET (ZM) proteins are a group of fusion proteins identified in human gliomas by high-throughput transcriptome sequencing. ZM fusions are associated with poor prognosis in afflicted glioma patients and mediate oncogenic effects in assays. In this study, we show that ZM-carrying patients have increased hepatocyte growth factor receptor (MET) mRNA expression levels induced by fusion with receptor-type tyrosine-protein phosphatase zeta (PTPRZ1). Furthermore, ZM fusions preserve fundamental properties of wild-type MET with respect to processing and dimerization, and enhance phosphorylation in an hepatocyte growth factor (HGF)-dependent and independent manner. Our findings suggest that ZM induces gliomas through elevated expression and phosphorylation of the MET oncoprotein.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-met/genética , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/genética , Western Blotting , Células HEK293 , Factor de Crecimiento de Hepatocito/farmacología , Humanos , Proteínas de Fusión Oncogénica/química , Proteínas de Fusión Oncogénica/metabolismo , Fosforilación/efectos de los fármacos , Multimerización de Proteína , Proteínas Proto-Oncogénicas c-met/química , Proteínas Proto-Oncogénicas c-met/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/química , Proteínas Tirosina Fosfatasas Clase 5 Similares a Receptores/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
PURPOSE: Isocitrate dehydrogenase (IDH) gene mutation is one of the most exciting new advances in these years. It has been reported that IDH gene frequently altered in grade II and grade III gliomas. We aimed to identify the mutation frequency of IDH genes in Chinese anaplastic glioma patients, the association of IDH gene mutation with other clinical and molecular pathological features and the prognostic value of it. METHODS: We performed polymerase chain reaction-based IDH gene mutation detection in 203 anaplastic glioma patients from China. RESULTS: A total of 108 and 3 patients harbored IDH1 and IDH2 gene mutation, respectively. And there was a higher proportion of MGMT promoter methylation, frontal lobe location, and better outcome and lower proportion of temporal location in IDH-mutated samples. There were hardly any significant association between protein expression level of well-known markers and IDH mutation. Anaplastic oligoastrocytoma and anaplastic astrocytoma patients with IDH gene mutation showed similar prognosis with anaplastic oligodendroglioma patients with wild-type IDH gene. CONCLUSIONS: IDH gene mutation is a good prognostic marker and a potential substratification factor for anaplastic glioma patients.