A tailored next‐generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas
Open Access
- 4 August 2020
- journal article
- research article
- Published by Wiley in Cancer Science
- Vol. 111 (10), 3902-3911
- https://doi.org/10.1111/cas.14597
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 Ⅳ 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 = 0.001). Hierarchical molecular classification of IDH‐wildtype glioblastomas revealed three 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 = 0.021), higher Ki‐67 score (p = 0.007), poor prognosis (p =0.012), 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.Keywords
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