Correction to: LTBP1 plays a potential bridge between depressive disorder and glioblastoma.

An amendment to this paper has been published and can be accessed via the original article.

LTBP1 plays a potential bridge between depressive disorder and glioblastoma.

BACKGROUND: Glioblastoma multiforme (GBM) is the most malignant tumor in human brain. Diagnosis and treatment of GBM may lead to psychological disorders such as depressive and anxiety disorders. There was no research focusing on the correlation between depressive/anxiety disorder and the outcome of GBM. Thus, the aim of this study was to investigate the possibility of depressive/anxiety disorder correlated with the outcome of GBM patients, as well as the overlapped mechanism bridge which could link depressive/anxiety disorders and GBM. METHODS: Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder (GAD-7) were used to investigate the psychological condition of GBM patients in our department. To further explore the potential mechanism, bioinformatic methods were used to screen out genes that could be indicators of outcome in GBM, followed by gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and protein-protein interaction (PPI) analysis. Further, cellular experiments were conducted to evaluate the proliferation, migration capacity of primary GBM cells from the patients. RESULTS: It was revealed that patients with higher PHQ-9 and GAD-7 scores had significantly worse prognosis than their lower-scored counterparts. Bioinformatic mining revealed that LTBP1 could be a potential genetic mechanism in both depressive/anxiety disorder and GBM. Primary GBM cells with different expression level of LTBP1 should significantly different proliferation and migration capacity. GO, KEGG analysis confirmed that extracellular matrix (ECM) was the most enriched function of LTBP1. PPI network showed the interaction of proteins altered by LTBP1. Hub genes COL1A2, COL5A1 and COL10A1, as well as mesenchymal marker CD44 and Vimentin were statistically higher expressed in LTBP1 high group; while proneural marker E-cadherin was significantly higher expressed in low LTBP1 group. CONCLUSION: There is closely correlation between depressive/anxiety disorders and GBM. LTBP1 could be a potential bridge linking the two diseases through the regulation of ECM.

Aging-related tumor associated fibroblasts changes could worsen the prognosis of GBM patients.

Background: Glioblastoma multiforme (GBM) is the most malignant tumor in human brain, with highly heterogeneity among different patients. Age could function as an incidence and prognosis risk factor for many tumors. Method: A series of bioinformatic experiments were conducted to evaluate the differences of incidence, differential expressed genes, enriched pathways with the data from Surveillance, Epidemiology, and End Results (SEER) program, the cancer genome atlas (TCGA) and Chinese glioma genome atlas (CGGA) project. Results: We discovered in our present study that distinct difference of incidence and prognosis of different aged GBM patients. By a series of bioinformatic method, we found that the tumor associated fibroblasts (TAFs) was the most crucial tumor microenvironment (TME) component that led to this phenomenon. Epithelial-mesenchymal transition (EMT) could be the mechanism by which TAFs regulate the progression of GBM. Conclusion: We have proposed a close correlation between age and GBM incidence and prognosis, and propose the underlying mechanism behind this correlation by mining different databases, which laid the foundation for future research.

Transcriptomic Analysis of Glioma Based on IDH Status Identifies ACAA2 as a Prognostic Factor in Lower Grade Glioma.

BACKGROUND: Glioma is the most common and lethal tumor in the central nervous system (CNS). More than 70% of WHO grade II/III gliomas were found to harbor isocitrate dehydrogenase (IDH) mutations which generated targetable metabolic vulnerabilities. Focusing on the metabolic vulnerabilities, some targeted therapies, such as NAMPT, have shown significant effects in preclinical and clinical trials. METHODS: We explored the TCGA as well as CGGA database and analyzed the RNA-seq data of lower grade gliomas (LGG) with the method of weighted correlation network analysis (WGCNA). Differential expressed genes were screened, and coexpression relationships were grouped together by performing average linkage hierarchical clustering on the topological overlap. Clinical data were used to conduct Kaplan-Meier analysis. RESULTS: In this study, we identified ACAA2 as a prognostic factor in IDH mutation lower grade glioma with the method of weighted correlation network analysis (WGCNA). The difference of ACAA2 gene expressions between the IDH wild-type (IDH-WT) group and the IDH mutant (IDH-MUT) group suggested that there may be different potential targeted therapies based on the fatty acid metabolic vulnerabilities, which promoted the personalized treatment for LGG patients.

Preoperative Changes in Hematological Markers and Predictors of Glioma Grade and Survival.

Background: Preoperative hematological markers that indicate nutritional, coagulation, and inflammation statuses have prognostic value for gliomas. This study aimed to investigate hematological markers with regard to tumor grades, isocitrate dehydrogenase mutations (IDH), age, and sex in patients with gliomas. Methods: From 2008 to 2017, patients with a pathological diagnosis of glioma who underwent surgery were retrospectively enrolled in this study. Information from clinical records, including age, sex, preoperative experiment tests (routine blood tests, biochemistry, and coagulation examinations), pathological results, and IDH status, was collected. A univariable survival analysis was performed. Hematological factors such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte-ratio (PLR), and albumin-to-globulin (AGR) were calculated. The prognostic nutrition index (PNI) was calculated as 10 × serum albumin value (g/dl) + 0.005 × peripheral lymphocyte count (per mm3). Results: Our study included 706 patients. The univariate analysis showed that age, IDH-1, and hematological factors were all significantly associated with overall survival (OS) in patients with gliomas. Our results showed that inflammation markers (NLR, PLR, and fibrinogen) were positively associated with age, whereas AGR was negatively associated with age. The PLR was significantly increased, whereas the AGR and PNI were decreased in women with gliomas, as compared with men. We found that inflammation markers increased and nutrition markers decreased with gliomas grade. However, these hematological markers did not significantly differ with IDH status. NLR was the best single hematological marker for distinguishing glioblastoma (GBM) [0.684 (0.645-0.723)], IDH-wt GBM [0.672 (0.631-0.71)] from other gliomas subtypes. Combinations of age with PNI and age with AGR were the best predictors of GBM [0.750 (0.713-0.786)] and IDH-wt GBM [0.759 (0.719-0.798)], respectively. Conclusion: Preoperative hematological marker levels vary among glioma grades and have high predictive values for GBM.

Higher Plasma Fibrinogen Levels are Associated with Malignant Phenotype and Worse Survival in Patients with Glioblastomas.

Preoperative plasma fibrinogen levels were associated with poor clinical outcomes in malignancies. There were few data about the prognostic value of plasma fibrinogen in glioblastomas (GBMs). The objective of our study was to investigate the association between fibrinogen and patients' clinicopathological factors and overall survival (OS). From 2008 to 2016, 315 patients with GBMs who had a surgical treatment at our institute, were retrospectively involved in this study. IDH (isocitrate dehydrogenase) mutations and ATRX (alpha thalassemia/mental retardation syndrome X-linked) loss were detected with IHC (Immunohistochemistry). The preoperative plasma fibrinogen levels ranged from 1.00 to 5.22 g/L, with a mean of were 2.57 g/L. There were increased levels of plasma fibrinogen in patients aged ≥ 65 years, secondary GBMs, IDH mutation (p = 0.033) and ATRX loss (p = 0.040). Moreover, the plasma fibrinogen level was the highest in the subtype of IDH-1R132H wildtype - ATRX expression, which showed a shorter OS compared to the group of IDH-1R132H mut and IDH-1R132H wildtype - ATRX loss (p = 0.001, log-rank test). ROC curves for fibrinogen and IDH-1R132H wildtype - ATRX expression was also plotted, and indicated a potential diagnostic value of fibrinogen in molecular pathology. Univariate analysis found that younger age, higher KPS (Karnofsky Performance Score), gross total resection, complete chemoradiotherapy, IDH-1R132H mutations and lower levels of fibrinogen were associated with favorable outcomes. Multivariate analysis proved that chemoradiotherapy, IDH-1R132H and fibrinogen were independent prognostic factors. In conclusion, plasma fibrinogen could predict clinical outcome and molecular subtype in GBMs.

Preoperative inflammation markers and IDH mutation status predict glioblastoma patient survival.

Recent studies suggest that inflammation response biomarkers are prognostic indicators of solid tumor outcomes. Here, we quantify the prognostic value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in glioblastomas (GBMs), taking into consideration the role of the isocitrate dehydrogenase (IDH) mutation status. We examined 141 primary glioblastomas (pGBMs) and 25 secondary glioblastomas (sGBMs). NLRs, PLRs, and LMRs were calculated before surgery. IDH mutations were detected immunohistochemically after tumor resection, and patients' clinical outcomes were analyzed after classification into GBM, pGBM, and IDH-wild type glioblastoma (IDH-wt GBM) groups. To make comparisons, we set cutoffs for NLR, PLR and LMR of 4.0, 175.0, and 3.7, respectively. In a multivariate analysis, both NLR (HR=1.712, 95% CI 1.026-2.858, p=0.040) and PLR (HR=2.051, 95% CI 1.288-3.267, p=0.002) had independent prognostic value. While a low NLR was associated with a better prognosis only in the IDH-wt GBM group, PLR was predictive of patient survival in the GBM, pGBM, and IDH-wt GBM groups. By contrast, LMR exhibited no prognostic value for any of the 3 types of GBM.

IDH-1R132H mutation status in diffuse glioma patients: implications for classification.

WHO2007 grading of diffuse gliomas in adults is well-established. However, IDH mutations make classification of gliomas according to the WHO2007 edition controversial. Here, we characterized IDH-1R132H mut status in a cohort of 670 adult patients with different WHO2007 grades of diffuse glioma. Patient characteristics, clinical data and prognoses were obtained from medical records. Patients with IDH-1R132H mut were younger and had better clinical outcomes than those without mutations. Differences in age among patients with astrocytomas of different WHO2007 grades were eliminated after patients were grouped based on IDH-1R132H status. IDH-1R132H mut was present more often in patients with lower Ki-67 and MGMT protein levels and higher mutant p53 levels. Ki-67 was also strongly associated with WHO2007 grade independently of IDH-1R132H mut status. Moreover, patients with Ki-67<30 survived longer than those with Ki-67≥30, regardless of IDH-1R132H mut status. Patients in the IDH-1R132H mut group with lower MGMT protein levels also had better clinical outcomes than those in other groups. Our results indicate that to better treat gliomas, IDH mutation status should be included when determining WHO2007 grade in glioma patients.