angiotensinogen and Brain-Neoplasms

Astrocytoma is the most common type of primary brain tumor. The risk factors for astrocytoma are poorly understood; however, germline genetic variants account for 25% of the risk of developing gliomas. In this study, we assessed the risk of astrocytoma associated with variants in AGT, known by its role in angiogenesis, TP53, a well-known tumor suppressor and the DNA repair gene MGMT in a Mexican population. A case-control study was performed in 49 adult Mexican patients with grade II-IV astrocytoma. Sequencing of exons and untranslated regions of AGT, MGMT, and TP53 from was carried in an Ion Torrent platform. Individuals with Mexican Ancestry from the 1000 Genomes Project were used as controls. Variants found in our cohort were then assessed in a The Cancer Genome Atlas astrocytoma pan-ethnic validation cohort. Variants rs1926723 located in AGT (OR 2.74, 1.40-5.36 95% CI), rs7896488 in MGMT (OR 3.43, 1.17-10.10 95% CI), and rs4968187 in TP53 (OR 2.48, 1.26-4.88 95% CI) were significantly associated with the risk of astrocytoma after multiple-testing correction. This is the first study where the AGT rs1926723 variant, TP53 rs4968187, and MGMT rs7896488 were found to be associated with the risk of developing an astrocytoma.

Topics: Adult; Angiotensinogen; Astrocytoma; Brain Neoplasms; Case-Control Studies; Cohort Studies; DNA Modification Methylases; DNA Repair Enzymes; Female; Gene Expression Regulation, Neoplastic; Genetic Variation; Humans; Male; Mexico; Middle Aged; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Patients with recurrent glioblastoma achieving response to bevacizumab combined with chemotherapy have clinical improvement and prolonged survival. High gene expression of angiotensinogen (AGT) is associated with a poor bevacizumab response. Because AGT expression is epigenetically regulated, we aimed to investigate whether AGT promoter methylation in tumor tissue predicts response to bevacizumab combination therapy in patients with recurrent glioblastoma. The study included 159 patients with recurrent glioblastoma, treated with bevacizumab combination treatment (training cohort, n = 77; validation cohort, n = 82). All patients could be evaluated for treatment response and biomarkers. DNA methylation of 4 CpG sites in the AGT promoter was measured using pyrosequencing. A model for nonresponse was established using logistic regression analysis. In the training cohort, lower methylation of each of the four CpG sites in the AGT promoter was significantly associated with nonresponse (all P < 0.05). Moreover, the mean methylation level of all four CpG sites was associated with an increased likelihood of not achieving response to bevacizumab combination therapy (twofold decrease: odds ratio = 3.01; 95% confidence interval: 1.41-6.44; P = 0.004). We developed a model for nonresponse in the training cohort, where a threshold of mean AGT promoter methylation levels was set to below 12%. The model could predict bevacizumab nonresponse with 96% specificity. Importantly, this predictor was also significantly associated with nonresponse in the validation cohort (P = 0.037). Taken together, our findings suggest that low AGT promoter methylation in tumor tissue predicts nonresponse to bevacizumab combination treatment in patients with recurrent glioblastoma. We have, thus, established and successfully validated a predictor for nonresponse that can be used to identify patients who will not benefit from bevacizumab combination therapy.

Topics: Adult; Aged; Angiotensinogen; Antineoplastic Agents, Immunological; Bevacizumab; Biomarkers, Tumor; Brain Neoplasms; Cohort Studies; CpG Islands; DNA Methylation; Female; Glioblastoma; Humans; Logistic Models; Male; Middle Aged; Neoplasm Recurrence, Local; Promoter Regions, Genetic; Renin-Angiotensin System

Renin-angiotensin system (RAS) in brain cancer represents a scarcely explored field in neuro-oncology. Recently, some pre- and clinical studies have reported that RAS components play a relevant role in the development and behavior of gliomas. The angiotensinogen (AGT) rs5050 genetic variant has been identified as a crucial regulator of the transcription of AGT mRNA, which makes it a logical and promising target of research. The aim of this study was to determine the relationship between the AGT rs5050 genetic variant in blood with prognosis in astrocytoma.. A prospective pilot study was performed on forty-eight astrocytoma patients, who received the standard-of-care treatment. Blood samples were taken prior to surgery and DNA was sequenced using Ion Torrent next-generation sequencing and analyzed by Ion Reporter software. Descriptive, bivariate, multivariate, and survival analyses were performed using SPSS v21, STATA 12 and GraphPad Prism 7.. Median follow-up was 41 months (range 1-48). Survival analysis showed a significant difference between the rs5050 genotypes (p = .05). We found lower survival rates in individuals with the GG-genotype of rs5050 AGT compared to patients with the TT- and TG-genotype (2 months vs. 11.5 months, respectively [p = .01]). In bivariate and multivariate analyses, GG-genotype was negatively associated with survival.. In patients with astrocytoma, AGT rs5050 GG-genotype was associated with poor prognosis. We propose this germline genetic variant as a complementary biomarker, which can be detected practically and safely in blood samples or saliva.

Topics: Adult; Aged; Angiotensinogen; Astrocytoma; Biomarkers, Tumor; Brain Neoplasms; Female; Follow-Up Studies; Gene Frequency; Genetic Predisposition to Disease; Germ-Line Mutation; Humans; Male; Middle Aged; Pilot Projects; Prognosis; Prospective Studies; Survival Analysis; Young Adult

Bevacizumab combination therapy is among the most frequently used treatments in recurrent glioblastoma and patients who achieve response to bevacizumab have improved survival as well as quality of life. Accordingly, the aim of this study was to identify predictive biomarkers for bevacizumab response in recurrent glioblastoma patients.. The study included a total of 82 recurrent glioblastoma patients treated with bevacizumab combination therapy whom were both response and biomarker evaluable. Gene expression of tumor tissue was analyzed by using a customized NanoString platform covering 800 genes. Candidate gene predictors associated with response were analyzed by multivariate logistic and Cox regression analysis.. Two genes were independently associated with response: Low expression of angiotensinogen (2-fold decrease in AGT; OR = 2.44; 95% CI: 1.45-4.17; P = 0.0009) and high expression of a HLA class II gene (2-fold increase in HLA-DQA1; OR = 1.22; 95% CI: 1.01-1.47; P = 0.04). These two genes were included in a model that is able predict response to bevacizumab combination therapy in clinical practice. When stratified for a validated prognostic index, the predictive model for response was significantly associated with improved overall survival.. Two genes (low angiotensinogen and high HLA-class II expression) were predictive for bevacizumab response and were included in a predictive model for response. This model can be used in clinical practice to identify patients who will benefit from bevacizumab combination therapy.

Topics: Adult; Aged; Angiotensinogen; Bevacizumab; Biomarkers, Tumor; Brain Neoplasms; Disease-Free Survival; Female; Glioblastoma; Histocompatibility Antigens Class II; Humans; Immunohistochemistry; Male; Middle Aged; Multivariate Analysis; Neoplasm Recurrence, Local; Prognosis; Treatment Outcome; Young Adult

Brain tumors, benign or malignant, are characterized by a very high degree of vascularization. Recent accumulating evidence suggests that during development the neuronal wiring follows the same routes as the vasculature and that these two systems may share some of the same factors for guidance. Thus, expression of dual angiogenic/neurogenic growth factors was evaluated by in situ hybridization in human primary brain tumors of three different types, i.e., astrocytomas, oligodendrogliomas, and ependymomas, of increasing grades, in relation with the grade and type of the tumor. For this evaluation we selected vascular endothelial growth factor (VEGF-A) and its receptors VEGF-R1 and VEGF-R2 and the neuropilins 1 and 2 (NRP-1 and NRP-2), which have proangiogenic properties, platelet-derived growth factor (PDGF) receptor-beta (PDGF-Rβ), which is required for the functional maturation of blood vessels, the ephrins and their Eph receptors, angiotensinogen (AGT) and thrombospondin-2 (TSP-2), which have potential antiangiogenic properties, and netrin-1 (Net-1), which regulates vascular architecture. We show that the expression of the VEGF-NRP system, PDGF-Rβ, TSP-2, AGT, and Net-1 are differentially regulated, either increased or decreased, in relation with the type and grade of the tumor, whereas regulation of the ephrinB system does not seem to be relevant in these human brain tumors.

Topics: Angiogenic Proteins; Angiotensinogen; Brain Neoplasms; Humans; In Situ Hybridization; Intercellular Signaling Peptides and Proteins; Neoplasm Grading; Neuropilin-1; Neuropilin-2; Oncogene Proteins; Receptor, Platelet-Derived Growth Factor beta; Retrospective Studies; RNA Probes; RNA, Messenger; Thrombospondins; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factor Receptor-2

The expression and function in growth and apoptosis of the renin-angiotensin system (RAS) was evaluated in human glioblastoma. Renin and angiotensinogen (AGT) mRNAs and proteins were found by in situ hybridisation and immunohistochemistry in glioblastoma cells. Angiotensinogen was present in glioblastoma cystic fluids. Thus, human glioblastoma cells produce renin and AGT and secrete AGT. Human glioblastoma and glioblastoma cells expressed renin, AGT, renin receptor, AT(2) and/or AT(1) mRNAs and proteins determined by RT-PCR and/or Western blotting, respectively. The function of the RAS in glioblastoma was studied using human glioblastoma cells in culture. Angiotensinogen, des(Ang I)AGT, tetradecapaptide renin substrate (AGT1-14), Ang I, Ang II or Ang III, added to glioblastoma cells in culture, did not modulate their proliferation, survival or death. Angiotensin-converting enzyme inhibitors did not diminish glioblastoma cell proliferation. However, the addition of selective synthetic renin inhibitors to glioblastoma cells decreased DNA synthesis and viable tumour cell number, and induced apoptosis. This effect was not counterbalanced by concomitant addition of Ang II. In conclusion, the complete RAS is expressed by human glioblastomas and glioblastoma cells in culture. Inhibition of renin in glioblastoma cells may be a potential approach to control glioblastoma cell proliferation and survival, and glioblastoma progression in combination therapy.

Topics: Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Apoptosis; Brain Neoplasms; Cell Division; CHO Cells; Cricetinae; Glioblastoma; Humans; Immunoenzyme Techniques; In Situ Hybridization; Protease Inhibitors; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin; Retrospective Studies; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Serine Proteinase Inhibitors; Tumor Cells, Cultured

Capillary hemangioblastoma is a tumor known to be associated with secondary polycythemia. Therefore, specimens from ten hemangioblastomas were studied by immunohistochemistry for the presence of erythropoietin, renin substrate, and for various endothelial, histiocytic and glial markers. In all tumors scattered cells among the stromal cells showed a positive-staining reaction with both anti-erythropoietin and anti-renin substrate. The same cells also stained positively for alpha-1-anti-trypsin. It is concluded that, in addition to the capillary endothelial cells, pericytes and stromal cells, capillary hemangioblastomas harbor cells containing and perhaps producing renin substrate and/or erythropoietin or a substance with similar antigenic determinants.

Topics: Angiotensinogen; Brain Neoplasms; Cerebellar Neoplasms; Erythropoietin; Hemangiosarcoma; Humans; Immunologic Techniques; Medulla Oblongata

Topics: Angiotensinogen; Antibodies; Brain Neoplasms; Cross Reactions; Electrophoresis, Polyacrylamide Gel; Erythropoietin; Female; Fluorescent Antibody Technique; Hemangiosarcoma; Humans; Molecular Weight; Radioimmunoassay