Novel molecular subtypes of intracranial germ cell tumors expand therapeutic opportunities

作者：Bo Li, Shuang Zhao, Shouwei Li, Chunde Li, Wei Liu, Lin Li, Bowen Cui, Xing Liu, Huiyuan Chen, Jing Zhang, Yin Ren, Fei Liu, Ming Yang, Tao Jiang, Yu Liu, Xiaoguang Qiu · 发表于：Neuro-Oncology · 年份：2024 · DOI：10.1093/neuonc/noae038 · 被引用次数：19 · 研究领域：Glioma Diagnosis and Treatment、Testicular diseases and treatments、Epilepsy research and treatment

BACKGROUND: Intracranial germ cell tumors (IGCTs) are a rare group of malignancies that are clinically classified as germinomas and nongerminomatous germ cell tumors (NGGCTs). Previous studies have found that somatic mutations involving the mitogen-activated protein kinase/mTOR signaling pathway are common early events. However, a comprehensive genomic understanding of IGCTs is still lacking. METHODS: We established a cohort including over 100 IGCTs and conducted genomic and transcriptomic sequencing. RESULTS: We identified novel recurrent driver genomic aberrations, including USP28 truncation mutations and high-level copy number amplification of KRAS and CRKL caused by replication of extrachromosomal DNA. Three distinct subtypes associated with unique genomic and clinical profiles were identified with transcriptome analysis: Immune-hot, MYC/E2F, and SHH. Both immune-hot and MYC/E2F were predominantly identified in germinomas and shared similar mutations involving the RAS/MAPK signaling pathway. However, the immune-hot group showed an older disease onset age and a significant immune response. MYC/E2F was characterized by a younger disease onset age and increased genomic instability, with a higher proportion of tumors showing whole-genome doubling. Additionally, the SHH subtype was mostly identified in NGGCTs. CONCLUSIONS: Novel genomic aberrations and molecular subtypes were identified in IGCTs. These findings provide molecular basis for the potential introduction of new trea...