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

Autor:	Leclair NK; Graduate Program in Genetics and Development, UConn Health, Farmington, CT, USA.; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA., Choudury A; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA,USA.; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA,USA., Chen WC; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA,USA.; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA,USA., Magill ST; Department of Neurological Surgery, Northwestern University, Chicago, IL, USA., McCortney K; Department of Neurological Surgery, Northwestern University, Chicago, IL, USA., Horbinski CM; Department of Pathology, Northwestern University, Chicago, IL, USA.; Department of Neurological Surgery, Northwestern University, Chicago, IL, USA., Chen Z; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA,USA.; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA,USA., Goldschmidt E; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA,USA., Eaton CD; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA,USA.; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA,USA., Bulsara KR; Division of Neurosurgery, Department of Surgery, UConn Health, Farmington, CT, USA., Bi WL; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Neurosurgery, Brigham and Women's Hospital, Boston, MA, USA., Patel AJ; Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA.; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.; Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA., Sahm F; CCU Neuropathology, German Consortium for Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany.; Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany., Raleigh D; Department of Pathology, University of California San Francisco, San Francisco, CA, USA.; Department of Neurological Surgery, University of California San Francisco, San Francisco, CA,USA.; Department of Radiation Oncology, University of California San Francisco, San Francisco, CA,USA., Anczukow O; Institute for Systems Genomics, UConn Health, Farmington, CT, USA.; Department of Genetics and Genome Sciences, UConn Health, Farmington, CT, USA.; The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2024 Dec 05; Vol. 26 (12), pp. 2222-2236.
DOI:	10.1093/neuonc/noae150
Abstrakt:	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 splice-switching antisense oligonucleotides to target RNA splicing changes in NASP and MFF observed in hypermitotic meningiomas, providing a rationale for RNA-based therapeutic design. Conclusions: RNA splicing is an important driver of meningioma phenotypes that can be useful in prognosticating patients and as a potential exploit for therapeutic vulnerabilities. (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
Databáze:	MEDLINE
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