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

  • Beyer U Department of Human Genetics OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
  • Brand F Department of Human Genetics OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
  • Martens H Department of Human Genetics OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
  • Weder J Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany.
  • Christians A Division of Neuropathology, Hannover Medical School, Hannover, Germany.
  • Elyan N Department of Human Genetics OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
  • Hentschel B Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
  • Westphal M Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Schackert G Department of Neurosurgery, Technical University Dresden, Dresden, Germany.
  • Pietsch T Department of Neuropathology, University of Bonn Medical School, Bonn, Germany.
  • Hong B Department of Neurosurgery, Hannover Medical School, Hannover, Germany.
  • Krauss JK Department of Neurosurgery, Hannover Medical School, Hannover, Germany.
  • Samii A Department of Neurosurgery, International Neuroscience Institute, Hannover, Germany.
  • Raab P Department of Neuroradiology, Hannover Medical School, Hannover, Germany.
  • Das A Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
  • Dumitru CA Department of Neurosurgery, Nordstadt Hospital, Hannover, Germany.
  • Sandalcioglu IE Department of Neurosurgery, Nordstadt Hospital, Hannover, Germany.
  • Hakenberg OW Department of Urology, University of Rostock, Rostock, Germany.
  • Erbersdobler A Institute of Pathology, University of Rostock, Rostock, Germany.
  • Lehmann U Institute of Pathology, Hannover Medical School, Hannover, Germany.
  • Reifenberger G Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany.
  • Weller M Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
  • Reijns MAM Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
  • Preller M Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany.
  • Wiese B Department of Neurology, Henriettenstift, Diakovere Krankenhaus gGmbH, Hannover, Germany.
  • Hartmann C Division of Neuropathology, Hannover Medical School, Hannover, Germany.
  • Weber RG Department of Human Genetics OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. weber.ruthild@mh-hannover.de.
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  • 2017-10-15
Published in:
  • Acta neuropathologica. - 2017
Aicardi–Goutières syndrome
Glioma
Prostate carcinoma
Type I interferon signaling
Whole-exome sequencing
Adenosine Deaminase
Adult
Animals
Cells, Cultured
Cohort Studies
DNA Modification Methylases
DNA Repair Enzymes
Female
Fibroblasts
Genetic Predisposition to Disease
Humans
Interferon Type I
Isocitrate Dehydrogenase
Male
Mice, Knockout
Molecular Dynamics Simulation
Neoplasms
Phenotype
Polymorphism, Single Nucleotide
Protein Stability
RNA-Binding Proteins
Ribonuclease H
Tumor Suppressor Proteins
English 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.
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  • English
Open access status
green
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https://sonar.rero.ch/global/documents/127298
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