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

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

Author information

1
Department of Human Genetics OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
2
Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany.
3
Centre for Structural Systems Biology, Hamburg, Germany.
4
Division of Neuropathology, Hannover Medical School, Hannover, Germany.
5
Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
6
Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
7
Department of Neurosurgery, Technical University Dresden, Dresden, Germany.
8
Department of Neuropathology, University of Bonn Medical School, Bonn, Germany.
9
Department of Neurosurgery, Hannover Medical School, Hannover, Germany.
10
Department of Neurosurgery, International Neuroscience Institute, Hannover, Germany.
11
Department of Neuroradiology, Hannover Medical School, Hannover, Germany.
12
Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.
13
Department of Neurosurgery, Nordstadt Hospital, Hannover, Germany.
14
Department of Urology, University of Rostock, Rostock, Germany.
15
Institute of Pathology, University of Rostock, Rostock, Germany.
16
Institute of Pathology, Hannover Medical School, Hannover, Germany.
17
Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany.
18
German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf and German Cancer Research Center (DKFZ), Heidelberg, Germany.
19
Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland.
20
Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
21
Department of Neurology, Henriettenstift, Diakovere Krankenhaus gGmbH, Hannover, Germany.
22
Department of Human Genetics OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. weber.ruthild@mh-hannover.de.

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

PMID:
29030706
DOI:
10.1007/s00401-017-1774-y
[Indexed for MEDLINE]
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