A Tailored Next-Generation Sequencing Panel Identified Distinct Subtypes Of Wildtype Idh And Tert Promoter Glioblastomas

Central nervous system tumors are classified based on an integrated diagnosis combining histology and molecular characteristics, includingIDH1/2andH3-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 inIDH1/2,TP53,PTEN,PDGFRA,NF1,RB1,CDKN2A/B,CDK4, and theTERTpromoter (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 56IDH-wildtype glioblastomas. Within theseIDH-wildtype glioblastomas, 33 samples (58.9%) showed a mutation inTERTp. Notably,PDGFRAmutations and their amplification were more commonly seen inTERTp-wildtype glioblastomas (43%) than inTERTp-mutant glioblastomas (6%) (P = .001). Hierarchical molecular classification ofIDH-wildtype glioblastomas revealed 3 distinct groups ofIDH-wildtype glioblastomas. One major cluster was characterized by mutations inPDGFRA, amplification ofCDK4andPDGFRA, homozygous deletion ofCDKN2A/B, and absence ofTERTpmutations. 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 ofIDH- andTERTp-wildtype glioblastomas with frequentPDGFRAalterations.