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A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas.

ABSTRACT: Central nervous system tumors are classified based on an integrated diagnosis combining histology and molecular characteristics, including IDH1/2 and H3-K27M mutations, as well as 1p/19q codeletion. Here, we aimed to develop and assess the feasibility of a glioma-tailored 48-gene next-generation sequencing (NGS) panel for integrated glioma diagnosis. We designed a glioma-tailored 48-gene NGS panel for detecting 1p/19q codeletion and mutations in IDH1/2, TP53, PTEN, PDGFRA, NF1, RB1, CDKN2A/B, CDK4, and the TERT promoter (TERTp). We analyzed 106 glioma patients (grade II: 19 cases, grade III: 23 cases, grade IV: 64 cases) using this system. The 1p/19q codeletion was detected precisely in oligodendroglial tumors using our NGS panel. In a cohort of 64 grade ? gliomas, we identified 56 IDH-wildtype glioblastomas. Within these IDH-wildtype glioblastomas, 33 samples (58.9%) showed a mutation in TERTp. Notably, PDGFRA mutations and their amplification were more commonly seen in TERTp-wildtype glioblastomas (43%) than in TERTp-mutant glioblastomas (6%) (P = .001). Hierarchical molecular classification of IDH-wildtype glioblastomas revealed 3 distinct groups of IDH-wildtype glioblastomas. One major cluster was characterized by mutations in PDGFRA, amplification of CDK4 and PDGFRA, homozygous deletion of CDKN2A/B, and absence of TERTp mutations. This cluster was significantly associated with older age (P = .021), higher Ki-67 score (P = .007), poor prognosis (P = .012), and a periventricular tumor location. We report the development of a glioma-tailored NGS panel for detecting 1p/19q codeletion and driver gene mutations on a single platform. Our panel identified distinct subtypes of IDH- and TERTp-wildtype glioblastomas with frequent PDGFRA alterations.

SUBMITTER: Higa N

PROVIDER: S-EPMC7541004 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas.

Higa Nayuta N Akahane Toshiaki T Yokoyama Seiya S Yonezawa Hajime H Uchida Hiroyuki H Takajo Tomoko T Kirishima Mari M Hamada Taiji T Matsuo Kei K Fujio Shingo S Hanada Tomoko T Hosoyama Hiroshi H Yonenaga Masanori M Sakamoto Akihisa A Hiraki Tsubasa T Tanimoto Akihide A Yoshimoto Koji K

Cancer science 20200906 10

Central nervous system tumors are classified based on an integrated diagnosis combining histology and molecular characteristics, including IDH1/2 and H3-K27M mutations, as well as 1p/19q codeletion. Here, we aimed to develop and assess the feasibility of a glioma-tailored 48-gene next-generation sequencing (NGS) panel for integrated glioma diagnosis. We designed a glioma-tailored 48-gene NGS panel for detecting 1p/19q codeletion and mutations in IDH1/2, TP53, PTEN, PDGFRA, NF1, RB1, CDKN2A/B, CD ...[more]

PMID: 32748499

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Project description:BackgroundDespite the advances in glioblastoma (GBM) treatment, the average life span of patients is 14 months. Therefore, it is urgent to identity biomarkers of prognosis, treatment response, or development of novel treatment strategies. We previously described the association of high epidermal growth factor-like domain multiple 7 (EGFL7) expression and unfavorable outcome of pilocytic astrocytoma patients. The present study aims to analyze the prognostic potential of EGFL7 in GBM isocitrate dehydrogenase (IDH)-wildtype, using immunohistochemistry and in silico approaches.MethodsSpearman's correlation analysis of The Cancer Genome Atlas RNA sequencing data was performed. The genes strongly correlated to EGFL7 expression were submitted to enrichment gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Additionally, EGFL7 expression was associated with patient overall survival. The expression of EGFL7 was analyzed through immunohistochemistry in 74 GBM IDH-wildtype patients' samples, and was associated with clinicopathological data and overall survival.ResultsIn silico analysis found 78 genes strongly correlated to EGFL7 expression. These genes were enriched in 40 biological processes and eight KEGG pathways, including angiogenesis/vasculogenesis, cell adhesion, and phosphoinositide 3-kinase-Akt, Notch, and Rap1 signaling pathways. The immunostaining showed high EGFL7 expression in 39 cases (52.7%). High immunolabelling was significantly associated with low Karnofsky Performance Status and poor overall survival. Cox analysis showed that GBMs IDH-wildtype with high EGFL7 expression presented a higher risk of death compared to low expression (hazard ratio, 1.645; 95% confidence interval, 1.021 to 2.650; p = .041).ConclusionsThis study gives insights regarding the genes that are correlated with EGFL7, as well as biological processes and signaling pathways, which should be further investigated in order to elucidate their role in glioblastoma biology.

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A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas.

Publications

A tailored next-generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas.

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