Recurrent PTPRZ1-MET fusion and a high occurrence rate of MET exon 14 skipping in brain metastases.

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.

Tumor microenvironment is associated with clinical and genetic properties of diffuse gliomas and predicts overall survival.

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.

Predicting the likelihood of postoperative seizure status based on mRNA sequencing in low-grade gliomas.

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.

RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas.

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.

A single aspergillus fumigatus intracranial abscess in an immunocompetent patient with parietal lobe tumorectomy.

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.

[Whole-genome messenger RNA profiling reveals genes involved in malignant progression of glioma].

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.

Comprehensive analysis of multi-omics data of recurrent gliomas identifies a recurrence-related signature as a novel prognostic marker.

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.

Mutation and Copy Number Alterations Analysis of KIF23 in Glioma.

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.

MET overexpression contributes to STAT4-PD-L1 signaling activation associated with tumor-associated, macrophages-mediated immunosuppression in primary glioblastomas.

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.

Prognostic Correlation of Autophagy-Related Gene Expression-Based Risk Signature in Patients with Glioblastoma.

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.