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

• Published in: Cancer science 2020-10, Vol.111 (10), p.3902-3911
• Main Authors: Higa, Nayuta, Akahane, Toshiaki, Yokoyama, Seiya, Yonezawa, Hajime, Uchida, Hiroyuki, Takajo, Tomoko, Kirishima, Mari, Hamada, Taiji, Matsuo, Kei, Fujio, Shingo, Hanada, Tomoko, Hosoyama, Hiroshi, Yonenaga, Masanori, Sakamoto, Akihisa, Hiraki, Tsubasa, Tanimoto, Akihide, Yoshimoto, Koji
• Format: Article
• Language: English
• Subjects: 1p/19q codeletion; Adult; Aged; Aged, 80 and over; Artificial chromosomes; Biomarkers; Brain cancer; Brain tumors; Central nervous system; Chromosome 19; Consortia; Cyclin-dependent kinase 4; Dehydrogenases; Deoxyribonucleic acid; Design; Diagnosis; DNA; Epidermal growth factor; Female; Gene deletion; Genes; Genetics, Genomics, and Proteomics; Genomes; Genomics; glioblastoma; Glioblastoma - classification; Glioblastoma - genetics; Glioblastoma - pathology; Glioma; High-Throughput Nucleotide Sequencing; Histology; Humans; Hybridization; Isocitrate Dehydrogenase - genetics; Kinases; Male; Middle Aged; Mutation; Neoplasm Proteins - genetics; next‐generation sequencing; Original; p53 Protein; Patients; PDGFRA alterations; Promoter Regions, Genetic - genetics; Proteins; PTEN protein; Receptor, Platelet-Derived Growth Factor alpha - genetics; Software; Taxonomy; Telomerase; Telomerase - genetics; TERT promoter; Tumors
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14597

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 = .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. A glioma‐tailored 48‐gene next‐generation sequencing panel identified distinct subtypes of wildtype IDH and TERT promoter glioblastomas with PDGFRA alterations.