RNA splicing as a biomarker and phenotypic driver of meningioma DNA-methylation groups

作者：Nathan K. Leclair, Abrar Choudury, William Chen, Stephen T. Magill, Kathleen McCortney, Craig Horbinski, Zhenhong Chen, Ezequiel Goldschmidt, Charlotte Eaton, Ketan R. Bulsara, Wenya Linda Bi, Akash J. Patel, Felix Sahm, David R. Raleigh, Olga Anczuków · 发表于：Neuro-Oncology · 年份：2024 · DOI：10.1093/neuonc/noae150 · 被引用次数：10 · 研究领域：Meningioma and schwannoma management、Chromatin Remodeling and Cancer、Glioma Diagnosis and Treatment

BACKGROUND: Advances in our understanding of the molecular biology of meningiomas have led to significant gains in the ability to predict patient prognosis and tumor recurrence and to identify novel targets for therapeutic design. Specifically, classification of meningiomas based on DNA methylation has greatly improved our ability to risk stratify patients, however new questions have arisen in terms of the underlying impact these DNA-methylation signatures have on meningioma biology. METHODS: This study utilizes RNA-sequencing data from 486 meningioma samples corresponding to 3 meningioma DNA-methylation groups (merlin-intact, immune-enriched, and hypermitotic), followed by in vitro experiments utilizing human meningioma cell lines. RESULTS: We identify alterations in RNA splicing between meningioma DNA-methylation groups including individual splicing events that correlate with hypermitotic meningiomas and predict tumor recurrence and overall patient prognosis and compile a set of splicing events that can accurately predict DNA-methylation classification based on RNA-seq data. Furthermore, we validate these events using reverse transcription polymerase chain reaction (RT-PCR) in patient samples and meningioma cell lines. Additionally, we identify alterations in RNA-binding proteins and splicing factors that lie upstream of RNA splicing events, including upregulation of SRSF1 in hypermitotic meningiomas which we show drives alternative RNA splicing changes. Finally, we design ...