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

Domenico Alessandro Silvestris, Ernesto Picardi, Valeriana Cesarini, Bruno Fosso, Nicolò Mangraviti, Luca Massimi, Maurizio Martini, Graziano Pesole, Franco Locatelli, Angela Gallo

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)33
JournalGenome Biology
Volume20
Issue number1
DOIs
Publication statusPublished - Feb 13 2019

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Glioblastoma
RNA
gender
stratification
RNA Editing
RNA editing
brain
Inosine
adenosine
Adenosine
sexual dimorphism
Brain
cancer
genomics
enzyme
gene therapy
gene
Sex Characteristics
Genetic Therapy
loci

Keywords

  • Adaptor Proteins, Vesicular Transport/genetics
  • Adenosine Deaminase/metabolism
  • Age Factors
  • Alu Elements
  • Astrocytes/metabolism
  • Brain/metabolism
  • Brain Neoplasms/genetics
  • Case-Control Studies
  • Cell Line, Tumor
  • Glioblastoma/genetics
  • HEK293 Cells
  • Humans
  • Inosine/metabolism
  • RNA Editing
  • Sex Factors

Cite this

Dynamic inosinome profiles reveal novel patient stratification and gender-specific differences in glioblastoma. / Silvestris, Domenico Alessandro; Picardi, Ernesto; Cesarini, Valeriana; Fosso, Bruno; Mangraviti, Nicolò; Massimi, Luca; Martini, Maurizio; Pesole, Graziano; Locatelli, Franco; Gallo, Angela.

In: Genome Biology, Vol. 20, No. 1, 13.02.2019, p. 33.

Research output: Contribution to journalArticle

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AU - Mangraviti, Nicolò

AU - Massimi, Luca

AU - Martini, Maurizio

AU - Pesole, Graziano

AU - Locatelli, Franco

AU - Gallo, Angela

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AB - 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.

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