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Acta Neuropathologica
Published in: Acta Neuropathologica 6/2017

01-12-2017 | Original Paper

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

Authors: Ulrike Beyer, Frank Brand, Helge Martens, Julia Weder, Arne Christians, Natalie Elyan, Bettina Hentschel, Manfred Westphal, Gabriele Schackert, Torsten Pietsch, Bujung Hong, Joachim K. Krauss, Amir Samii, Peter Raab, Anibh Das, Claudia A. Dumitru, I. Erol Sandalcioglu, Oliver W. Hakenberg, Andreas Erbersdobler, Ulrich Lehmann, Guido Reifenberger, Michael Weller, Martin A. M. Reijns, Matthias Preller, Bettina Wiese, Christian Hartmann, Ruthild G. Weber

Published in: Acta Neuropathologica | Issue 6/2017

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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.
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Metadata
Title
Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis
Authors
Ulrike Beyer
Frank Brand
Helge Martens
Julia Weder
Arne Christians
Natalie Elyan
Bettina Hentschel
Manfred Westphal
Gabriele Schackert
Torsten Pietsch
Bujung Hong
Joachim K. Krauss
Amir Samii
Peter Raab
Anibh Das
Claudia A. Dumitru
I. Erol Sandalcioglu
Oliver W. Hakenberg
Andreas Erbersdobler
Ulrich Lehmann
Guido Reifenberger
Michael Weller
Martin A. M. Reijns
Matthias Preller
Bettina Wiese
Christian Hartmann
Ruthild G. Weber
Publication date
01-12-2017
Publisher
Springer Berlin Heidelberg
Published in
Acta Neuropathologica / Issue 6/2017
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI
https://doi.org/10.1007/s00401-017-1774-y

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