Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma
Abstract 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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2019-02-01
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| Series: | Genome Biology |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13059-019-1647-x |
| _version_ | 1818266658824781824 |
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| author | Domenico Alessandro Silvestris Ernesto Picardi Valeriana Cesarini Bruno Fosso Nicolò Mangraviti Luca Massimi Maurizio Martini Graziano Pesole Franco Locatelli Angela Gallo |
| author_facet | Domenico Alessandro Silvestris Ernesto Picardi Valeriana Cesarini Bruno Fosso Nicolò Mangraviti Luca Massimi Maurizio Martini Graziano Pesole Franco Locatelli Angela Gallo |
| author_sort | Domenico Alessandro Silvestris |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-12T20:10:12Z |
| format | Article |
| id | doaj.art-0c90d1ec0eab48f48aac9a327593555b |
| institution | Directory Open Access Journal |
| issn | 1474-760X |
| language | English |
| last_indexed | 2024-12-12T20:10:12Z |
| publishDate | 2019-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Biology |
| spelling | doaj.art-0c90d1ec0eab48f48aac9a327593555b2022-12-22T00:13:32ZengBMCGenome Biology1474-760X2019-02-0120111810.1186/s13059-019-1647-xDynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastomaDomenico Alessandro Silvestris0Ernesto Picardi1Valeriana Cesarini2Bruno Fosso3Nicolò Mangraviti4Luca Massimi5Maurizio Martini6Graziano Pesole7Franco Locatelli8Angela Gallo9RNA Editing Lab., Oncohaematology Department, IRCCS Ospedale Pediatrico “Bambino Gesù”Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari “A. Moro”RNA Editing Lab., Oncohaematology Department, IRCCS Ospedale Pediatrico “Bambino Gesù”Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies (IBIOM), National Research CouncilRNA Editing Lab., Oncohaematology Department, IRCCS Ospedale Pediatrico “Bambino Gesù”Fondazione Policlinico Universitario “A. Gemelli,” IRCCS, UOC Neurochirurgia InfantileFondazione Policlinico Universitario “A. Gemelli”, IRCCS, UOC Anatomia PatologicaDepartment of Biosciences, Biotechnology and Biopharmaceutics, University of Bari “A. Moro”RNA Editing Lab., Oncohaematology Department, IRCCS Ospedale Pediatrico “Bambino Gesù”RNA Editing Lab., Oncohaematology Department, IRCCS Ospedale Pediatrico “Bambino Gesù”Abstract 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.http://link.springer.com/article/10.1186/s13059-019-1647-xRNA editingADARGBMRNA-SeqCOG3 |
| spellingShingle | Domenico Alessandro Silvestris Ernesto Picardi Valeriana Cesarini Bruno Fosso Nicolò Mangraviti Luca Massimi Maurizio Martini Graziano Pesole Franco Locatelli Angela Gallo Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma Genome Biology RNA editing ADAR GBM RNA-Seq COG3 |
| title | Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma |
| title_full | Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma |
| title_fullStr | Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma |
| title_full_unstemmed | Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma |
| title_short | Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma |
| title_sort | dynamic inosinome profiles reveal novel patient stratification and gender specific differences in glioblastoma |
| topic | RNA editing ADAR GBM RNA-Seq COG3 |
| url | http://link.springer.com/article/10.1186/s13059-019-1647-x |
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