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

Research output: Contribution to journalArticle

  • 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
  • Matthias Preller
  • Bettina Wiese
  • Christian Hartmann
  • Ruthild G Weber

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)905-922
Number of pages18
JournalActa Neuropathologica
Volume134
Issue number6
Early online date13 Oct 2017
DOIs
StatePublished - Dec 2017

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.

    Research areas

  • Journal Article

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