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Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma

BACKGROUND: Adenosine-to-inosine (A-to-I) RNA editing is an essential post-transcriptional mechanism mediated by ADAR enzymes that have been recently associated with cancer. RESULTS: Here, we characterize the inosinome signature in normal brain and de novo glioblastoma (GBM) using new metrics that r...

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Detalles Bibliográficos
Autores principales: Silvestris, Domenico Alessandro, Picardi, Ernesto, Cesarini, Valeriana, Fosso, Bruno, Mangraviti, Nicolò, Massimi, Luca, Martini, Maurizio, Pesole, Graziano, Locatelli, Franco, Gallo, Angela
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373152/
https://www.ncbi.nlm.nih.gov/pubmed/30760294
http://dx.doi.org/10.1186/s13059-019-1647-x
Descripción
Sumario:BACKGROUND: Adenosine-to-inosine (A-to-I) RNA editing is an essential post-transcriptional mechanism mediated by ADAR enzymes that have been recently associated with cancer. RESULTS: Here, we characterize the inosinome signature in normal brain and de novo glioblastoma (GBM) using new metrics that re-stratify GBM patients according to their editing profiles and indicate this post-transcriptional event as a possible molecular mechanism for sexual dimorphism in GBM. We find that over 85% of de novo GBMs carry a deletion involving the genomic locus of ADAR3, which is specifically expressed in the brain. By analyzing RNA editing and patient outcomes, an intriguing gender-dependent link appears, with high editing of Alus shown to be beneficial only in male patients. We propose an inosinome-based molecular stratification of GBM patients that identifies two different GBM subgroups, INO-1 and INO-2, which can identify novel high-risk gender-specific patient groups for which more aggressive treatments may be necessary. CONCLUSIONS: Our data provide a detailed picture of RNA editing landscape in normal brain and GBM, exploring A-to-I RNA editing regulation, disclosing unexpected editing implications for GBM patient stratification and identification of gender-dependent high-risk patients, and suggesting COG3 I/V as an eligible site for future personalized targeted gene therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13059-019-1647-x) contains supplementary material, which is available to authorized users.