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

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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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Acknowledgements

The authors wish to thank the patients and their families for participating in this study, and all colleagues, patients, and families supporting the German Glioma Network. We acknowledge Andrew P. Jackson, Edinburgh, UK for helpful discussions, Vanessa Dewor and Wiebke Schulze, Hannover, Germany for excellent technical assistance, and Alma Osmanovic, Hannover, Germany for performing the skin biopsy on patient II.2 of family 2. pCMV-HA-ADAR wild-type constructs and the pIRESneo vector were kindly provided by Yanick Crow, Manchester, UK and Paris, France, and Matthias Dobbelstein, Göttingen, Germany, respectively.

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Author notes

  1. Ulrike Beyer and Frank Brand have contributed equally as first authors to this work.

Authors and Affiliations

  1. Department of Human Genetics OE 6300, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany

    Ulrike Beyer, Frank Brand, Helge Martens, Natalie Elyan & Ruthild G. Weber

  2. Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany

    Julia Weder & Matthias Preller

  3. Centre for Structural Systems Biology, Hamburg, Germany

    Julia Weder & Matthias Preller

  4. Division of Neuropathology, Hannover Medical School, Hannover, Germany

    Arne Christians & Christian Hartmann

  5. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany

    Bettina Hentschel

  6. Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Manfred Westphal

  7. Department of Neurosurgery, Technical University Dresden, Dresden, Germany

    Gabriele Schackert

  8. Department of Neuropathology, University of Bonn Medical School, Bonn, Germany

    Torsten Pietsch

  9. Department of Neurosurgery, Hannover Medical School, Hannover, Germany

    Bujung Hong & Joachim K. Krauss

  10. Department of Neurosurgery, International Neuroscience Institute, Hannover, Germany

    Amir Samii

  11. Department of Neuroradiology, Hannover Medical School, Hannover, Germany

    Peter Raab

  12. Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany

    Anibh Das

  13. Department of Neurosurgery, Nordstadt Hospital, Hannover, Germany

    Claudia A. Dumitru & I. Erol Sandalcioglu

  14. Department of Urology, University of Rostock, Rostock, Germany

    Oliver W. Hakenberg

  15. Institute of Pathology, University of Rostock, Rostock, Germany

    Andreas Erbersdobler

  16. Institute of Pathology, Hannover Medical School, Hannover, Germany

    Ulrich Lehmann

  17. Department of Neuropathology, Heinrich-Heine-University, Düsseldorf, Germany

    Guido Reifenberger

  18. German Cancer Consortium (DKTK), Partner Site Essen/Düsseldorf and German Cancer Research Center (DKFZ), Heidelberg, Germany

    Guido Reifenberger

  19. Department of Neurology, University Hospital and University of Zurich, Zurich, Switzerland

    Michael Weller

  20. Medical Research Council Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

    Martin A. M. Reijns

  21. Department of Neurology, Henriettenstift, Diakovere Krankenhaus gGmbH, Hannover, Germany

    Bettina Wiese

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  1. Ulrike Beyer
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  2. Frank Brand
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Contributions

UB, FB, MAMR, MP, and RGW designed research; UB, FB, HM, JW, AC, NE, AE, MP, and CH performed research; BH, MaW, GS, TP, BH, JKK, AS, PR, AD, CAD, IES, OWH, AE, UL, GR, MiW, MAMR, BW, and CH contributed materials, patient/tumor data and expertise; UB, FB, JW, MP, and RGW analyzed data and made figures; UB, FB, MAMR, MP, and RGW wrote the manuscript; all authors reviewed and revised the manuscript.

Corresponding author

Correspondence to Ruthild G. Weber.

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Statement of human rights

The study was approved by the appropriate institutional research ethics committees. All procedures were in accordance with their ethical standards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Funding

This work was supported by the German Cancer Aid (Deutsche Krebshilfe e.V.; Grant No. 70-3163-Wi 3).

Conflict of interest

GR has received research grants from Roche and Merck (EMD, Darmstadt), as well as honoraria for lectures or advisory boards from Amgen, Celldex, and Medac. JKK is a consultant to Medtronic and Boston Scientific, and received fees for speaking from St. Jude Medical/AbbVie. All other authors declare that they have no conflict of interest.

Additional information

Bettina Hentschel, Manfred Westphal, Gabriele Schackert, Torsten Pietsch, Guido Reifenberger, and Michael Weller represent the German Glioma Network.

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Beyer, U., Brand, F., Martens, H. et al. Rare ADAR and RNASEH2B variants and a type I interferon signature in glioma and prostate carcinoma risk and tumorigenesis. Acta Neuropathol 134, 905–922 (2017). https://doi.org/10.1007/s00401-017-1774-y

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