Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis

Acta Neuropathol. 2017 Dec;134(6):905-922. doi: 10.1007/s00401-017-1774-y. Epub 2017 Oct 13.

Abstract

In search of novel germline alterations predisposing to tumors, in particular to gliomas, we studied a family with two brothers affected by anaplastic gliomas, and their father and paternal great-uncle diagnosed with prostate carcinoma. In this family, whole-exome sequencing yielded rare, simultaneously heterozygous variants in the Aicardi-Goutières syndrome (AGS) genes ADAR and RNASEH2B co-segregating with the tumor phenotype. AGS is a genetically induced inflammatory disease particularly of the brain, which has not been associated with a consistently increased cancer risk to date. By targeted sequencing, we identified novel ADAR and RNASEH2B variants, and a 3- to 17-fold frequency increase of the AGS mutations ADAR,c.577C>G;p.(P193A) and RNASEH2B,c.529G>A;p.(A177T) in the germline of familial glioma patients as well as in test and validation cohorts of glioblastomas and prostate carcinomas versus ethnicity-matched controls, whereby rare RNASEH2B variants were significantly more frequent in familial glioma patients. Tumors with ADAR or RNASEH2B variants recapitulated features of AGS, such as calcification and increased type I interferon expression. Patients carrying ADAR or RNASEH2B variants showed upregulation of interferon-stimulated gene (ISG) transcripts in peripheral blood as seen in AGS. An increased ISG expression was also induced by ADAR and RNASEH2B variants in tumor cells and was blocked by the JAK inhibitor Ruxolitinib. Our data implicate rare variants in the AGS genes ADAR and RNASEH2B and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis, consistent with a genetic basis underlying inflammation-driven malignant transformation in glioma and prostate carcinoma development.

Keywords: Aicardi–Goutières syndrome; Glioma; Prostate carcinoma; Type I interferon signaling; Whole-exome sequencing.

MeSH terms

  • Adenosine Deaminase / genetics*
  • Adenosine Deaminase / metabolism
  • Adult
  • Animals
  • Cells, Cultured
  • Cohort Studies
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / genetics
  • Female
  • Fibroblasts / metabolism
  • Genetic Predisposition to Disease*
  • Humans
  • Interferon Type I / metabolism*
  • Isocitrate Dehydrogenase / genetics
  • Male
  • Mice, Knockout
  • Molecular Dynamics Simulation
  • Neoplasms / drug therapy
  • Neoplasms / genetics*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Phenotype
  • Polymorphism, Single Nucleotide
  • Protein Stability
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Ribonuclease H / genetics*
  • Tumor Suppressor Proteins / genetics

Substances

  • Interferon Type I
  • RNA-Binding Proteins
  • Tumor Suppressor Proteins
  • Isocitrate Dehydrogenase
  • IDH1 protein, human
  • DNA Modification Methylases
  • MGMT protein, human
  • ribonuclease HII
  • Ribonuclease H
  • ADAR protein, human
  • Adenosine Deaminase
  • DNA Repair Enzymes