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Angiotensinogen rs5050 germline genetic variant as potential biomarker of poor prognosis in astrocytoma.

ABSTRACT: INTRODUCTION: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.

SUBMITTER: Perdomo-Pantoja A

PROVIDER: S-EPMC6211735 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Angiotensinogen rs5050 germline genetic variant as potential biomarker of poor prognosis in astrocytoma.

Perdomo-Pantoja Alexander A Mejía-Pérez Sonia Iliana SI Reynoso-Noverón Nancy N Gómez-Flores-Ramos Liliana L Soto-Reyes Ernesto E Sánchez-Correa Thalía Estefania TE Guerra-Calderas Lissania L Castro-Hernandez Clementina C Vidal-Millán Silvia S Sánchez-Corona José J Taja-Chayeb Lucia L Gutiérrez Olga O Cacho-Diaz Bernardo B Alvarez-Gomez Rosa Maria RM Gómez-Amador Juan Luis JL Ostrosky-Wegman Patricia P Corona Teresa T Herrera-Montalvo Luis Alonso LA Wegman-Ostrosky Talia T

PloS one 20181101 11

<h4>Introduction</h4>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 relation ...[more]

PMID: 30383794

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Project description:Diffuse IDH-mutant astrocytoma mostly occurs in adults and carries a favorable prognosis compared to IDH-wildtype malignant gliomas. Acquired mismatch repair deficiency is known to occur in recurrent IDH-mutant gliomas as resistance mechanism towards alkylating chemotherapy. In this multi-institutional study, we report a novel epigenetic group of 32 IDH-mutant gliomas with proven or suspected hereditary mismatch repair deficiency. None of the tumors exhibited a combined 1p/19q deletion. These primary mismatch repair-deficient IDH-mutant astrocytomas (PMMRDIA) were histologically high-grade and were mainly found in children, adolescents and young adults (median age 14 years). Mismatch repair deficiency syndromes (Lynch or Constitutional Mismatch Repair Deficiency Syndrom (CMMRD)) were clinically diagnosed and/or germline mutations in DNA mismatch repair genes (MLH1, MSH6, MSH2) were found in all cases, except one case with a family and personal history of colon cancer and another case with MSH6-deficiency available only as recurrent tumor. Loss of at least one of the mismatch repair proteins was detected via immunohistochemistry in all, but one case analyzed. Tumors displayed a hypermutant genotype and microsatellite instability was present in more than half of the sequenced cases. Integrated somatic mutational and chromosomal copy number analyses showed frequent inactivation of TP53, RB1 and activation of RTK/PI3K/AKT pathways. In contrast to the majority of IDH-mutant gliomas, more than 60% of the samples in our cohort presented with an unmethylated MGMT promoter. While the rate of immuno-histochemical ATRX loss was reduced, variants of unknown significance were more frequently detected possibly indicating a higher frequency of ATRX inactivation by protein malfunction. Compared to reference cohorts of other IDH-mutant gliomas, primary mismatch repair-deficient IDH-mutant astrocytomas have by far the worst clinical outcome with a median survival of only 15 months irrespective of histological or molecular features. The findings reveal a so far unknown entity of IDH-mutant astrocytoma with high prognostic relevance. Diagnosis can be established by aligning with the characteristic DNA methylation profile, by DNA-sequencing-based proof of mismatch repair deficiency or immunohistochemically demonstrating loss-of-mismatch repair proteins.

Project description:BackgroundApproximately 80% of lung cancers are non-small cell lung cancers (NSCLC). Lung adenocarcinoma (LUAD) is the main subtype of NSCLC. The incidence and mortality of lung cancer are also increasing yearly. Myogenic differentiation family inhibitor (MDFI) as a transcription factor, its role in lung cancer has not yet been clarified.MethodsLUAD data were downloaded from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO), analyzed and plotted using the R language. Associations between Clinical information and MDFI expression were assessed using logistic regression analyses to explore the effects of MDFI on LUAD. Two sets of tissue microarrays (TMAs) further confirmed the overexpression of MDFI in LUAD and its impact on prognosis. In addition, we examined the correlation between MDFI and immune infiltration. To investigate the effect of MDFI on the biological behavior of LUAD tumor cells by GSEA and GO/KEGG analysis. The survival status and somatic mutational characteristics of patients according to MDFI levels were depicted and analyzed.ResultsExpression of high MDFI in LUAD tissues via analyzing TCGA dataset (P <0.001). Kaplan-Meier survival analysis indicated a poor prognosis for those patients with LUAD who had upregulated MDFI expression levels (P <0.001). This was also verified by two groups of TMAs (P=0.024). Using logistic statistics analysis, MDFI was identified as an independent predictive factor and was associated with poor prognosis in LUAD (P <0.001, P =0.021). Assessment of clinical characteristics, tumor mutation burden (TMB), and tumor microenvironment (TME) between high- and low-expression score groups showed lower TMB, richer immune cell infiltration, and better prognosis in the low-risk group.ConclusionThis study showed that MDFI was overexpressed in LUAD and was significantly associated with poor prognosis, indicating that MDFI may be used as a potential novel biomarker for the diagnosis and prognosis of LUAD. MDFI is associated with immune infiltration of LUAD and it is reasonable to speculate that it plays an important role in tumor proliferation and spread. In view of the significant differences in MDFI expression between different biological activities, LUAD patients with MDFI overexpression may obtain more precise treatment strategies in the clinic.

Dataset Information

Angiotensinogen rs5050 germline genetic variant as potential biomarker of poor prognosis in astrocytoma.

Publications

Angiotensinogen rs5050 germline genetic variant as potential biomarker of poor prognosis in astrocytoma.

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