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Dissecting Molecular Features of Gliomas: Genetic Loci and Validated Biomarkers.

ABSTRACT: Recently, several studies focused on the genetics of gliomas. This allowed identifying several germline loci that contribute to individual risk for tumor development, as well as various somatic mutations that are key for disease classification. Unfortunately, none of the germline loci clearly confers increased risk per se. Contrariwise, somatic mutations identified within the glioma tissue define tumor genotype, thus representing valid diagnostic and prognostic markers. Thus, genetic features can be used in glioma classification and guided therapy. Such copious genomic variabilities are screened routinely in glioma diagnosis. In detail, Sanger sequencing or pyrosequencing, fluorescence in-situ hybridization, and microsatellite analyses were added to immunohistochemistry as diagnostic markers. Recently, Next Generation Sequencing was set-up as an all-in-one diagnostic tool aimed at detecting both DNA copy number variations and mutations in gliomas. This approach is widely used also to detect circulating tumor DNA within cerebrospinal fluid from patients affected by primary brain tumors. Such an approach is providing an alternative cost-effective strategy to genotype all gliomas, which allows avoiding surgical tissue collection and repeated tumor biopsies. This review summarizes available molecular features that represent solid tools for the genetic diagnosis of gliomas at present or in the next future.

SUBMITTER: Arcella A

PROVIDER: S-EPMC7014190 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Dissecting Molecular Features of Gliomas: Genetic Loci and Validated Biomarkers.

Arcella Antonietta A Limanaqi Fiona F Ferese Rosangela R Biagioni Francesca F Oliva Maria Antonietta MA Storto Marianna M Fanelli Mirco M Gambardella Stefano S Fornai Francesco F

International journal of molecular sciences 20200120 2

Recently, several studies focused on the genetics of gliomas. This allowed identifying several germline loci that contribute to individual risk for tumor development, as well as various somatic mutations that are key for disease classification. Unfortunately, none of the germline loci clearly confers increased risk per se. Contrariwise, somatic mutations identified within the glioma tissue define tumor genotype, thus representing valid diagnostic and prognostic markers. Thus, genetic features ca ...[more]

PMID: 31968687

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Project description:BackgroundGliomas account for the major part of primary brain tumors. Based on their histology and molecular alternations, adult gliomas have been classified into four grades, each with distinct biology and outcome. Previous studies have focused on cell-line-based models and patient-derived xenografts (PDXs) from patient-derived glioma cultures for grade IV glioblastoma. However, the PDX of lower grade diffuse gliomas, particularly those harboring the endogenous IDH mutation, are scarce due to the difficulty growing glioma cells in vitro and in vivo. The purpose of this study was to develop a panel of patient-derived subcutaneous xenografts of different grade gliomas that represented the heterogeneous histopathologic and genetic features of human gliomas.MethodsTumor pieces from surgical specimens were subcutaneously implanted into flanks of NOD-Prkdcscid ll2rgnull mice. Then, we analyzed the association between the success rate of implantation with clinical parameters using the Chi square test and resemblance to the patient's original tumor using immunohistochemistry, immunofluorescence, short tandem repeat analysis, quantitative real-time polymerase chain reaction, and whole-exome sequencing.ResultsA total of 11 subcutaneous xenografts were successfully established from 16 surgical specimens. An increased success rate of implantation in gliomas with wild type isocitrate dehydrogenase (IDH) and high Ki67 expression was observed compared to gliomas with mutant IDH and low Ki67 expression. Recurrent and distant aggressive xenografts were present near the primary implanted tumor fragments from WHO grades II to IV. The xenografts histologically represented the corresponding patient tumor and reconstituted the heterogeneity of different grade gliomas. However, increased Ki67 expression was found in propagated xenografts. Endothelial cells from mice in patient-derived xenografts over several generations replaced the corresponding human tumor blood vessels. Short tandem repeat and whole-exome sequencing analyses indicated that the glioma PDX tumors maintained their genomic features during engraftments over several generations.ConclusionsThe panel of patient-derived glioma xenografts in this study reproduced the diverse heterogeneity of different grade gliomas, thereby allowing the study of the growth characteristics of various glioma types and the identification of tumor-specific molecular markers, which has applications in drug discovery and patient-tailored therapy.

Project description:The present study aimed to evaluate the impact caused by the 2016 World Health Organization (WHO) diagnostic classification of gliomas in 139 patients studied in Argentina. Formalin-fixed paraffin-embedded tissues were used for histological and immunohistochemical analysis [glial fibrillary acidic protein, KI67, synaptophysin and isocitrate dehydrogenase (IDH)1-R132H]. DNA from formalin-fixed paraffin-embedded tissues was used for molecular analysis: 1p/19q co-deletion and mutation status of the IDH gene. These experiments were performed by direct Sanger sequencing and multiplex ligation-dependent probe amplification. According to the new classification, diagnoses included oligodendroglioma IDH-mutant and 1p/19q co-deletion (4.20%), anaplastic oligodendroglioma IDH-mutant and 1p/19q co-deletion (2.52%), diffuse astrocytoma IDH-mutant (6.72%), diffuse astrocytoma IDH-wild type (1.68%), anaplastic astrocytoma IDH-mutant (5.04%), anaplastic astrocytoma IDH-wild type (8.40%), glioblastoma IDH-mutant (5.88%) and glioblastoma IDH-wild type (65.56%). Regarding tumor histology, 60% of oligodendrogliomas, 35% of astrocytoma and 100% of unclassified gliomas were re-classified, while glioblastomas maintained their initial classification. Additionally, the present study evaluated the prognostic value of the histological grade for the 2007 and 2016 WHO classifications of gliomas. The histological subgroup associated with longer overall survival (OS) was grade II glioma (OS-2007WHO, 35.6 months; and OS-2016WHO, 47.7 months). Glioblastoma was the subgroup associated with a poor outcome (OS-2007WHO, 10.4 months; and OS-2016WHO, 11.1 months). The present study evaluated the OS of tumor grade subgroups with respect to their IDH status. For all subgroups, IDH-mutant tumors were associated with an improved prognosis compared with IDH-wild type tumors. The results suggested that the incorporation of molecular biomarkers in the new WHO classification improves tumor characterization and prognostic value of the subgroups.

Project description:Gliomas are among the most common intracranial tumors which originated from neuroepithelial cells. Increasing evidence has revealed that long noncoding RNA (lncRNA)-microRNA (miRNA)-mRNA module regulation and tumor-infiltrating immune cells play important regulatory roles in the occurrence and progression of gliomas. However, the precise underlying molecular mechanisms remain largely unknown. Data on gliomas in The Cancer Genome Atlas lack normal control samples; to overcome this limitation, we combined 665 The Cancer Genome Atlas glioma RNA sequence datasets with 188 Genotype-Tissue Expression normal brain RNA sequences to construct an expression matrix profile after normalization. We systematically analyzed the expression of mRNAs, lncRNAs, and miRNAs between gliomas and normal brain tissues. Kaplan-Meier survival analyses were conducted to screen differentially expressed mRNAs, lncRNAs, and miRNAs. A prognostic miRNA-related competitive endogenous RNA network was constructed, and the core subnetworks were filtered using 6 miRNAs, 3 lncRNAs, and 11 mRNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed to investigate the biological functions of significantly dysregulated mRNAs. Co-expression network analysis was performed to analyze and screen the core genes. Furthermore, single-sample Gene Set Enrichment Analysis and immune checkpoint gene expression analysis were performed, as co-expression analysis indicated immune gene dysregulation in glioma. Finally, the expression of representative dysregulated genes was validated in U87 cells at the transcriptional level, establishing a foundation for further research. We identified 7017 mRNAs, 437 lncRNAs, and 9 miRNAs that were differentially expressed in gliomas. Kaplan-Meier survival analysis revealed 5684 mRNAs, 61 lncRNAs, and 7 miRNAs with potential as prognostic signatures in patients with glioma. The hub subnetwork of the competing endogenous RNA network between PART1-hsa-mir-25-SLC12A5/TACC2/BSN/TLN2/ZDHHC8 was screened out. Gene co-expression network, single-sample Gene Set Enrichment Analysis, and immune checkpoint expression analysis demonstrated that tumor-infiltrating immune cells are closely related to gliomas. We identified novel potential biomarkers to predict survival and therapeutic targets for patients with gliomas based on a large-scale sample. Importantly, we filtered pivotal genes that provide valuable information for further exploration of the molecular mechanisms underlying glioma tumorigenesis and progression.

Dataset Information

Dissecting Molecular Features of Gliomas: Genetic Loci and Validated Biomarkers.

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Dissecting Molecular Features of Gliomas: Genetic Loci and Validated Biomarkers.

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