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

AbstractIn 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) genesADAR andRNASEH2B 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 novelADAR andRNASEH2B variants, and a 3- to 17-fold frequency increase of the AGS mutationsADAR,c.577C>G;p.(P193A) andRNASEH2B,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 rareRNASEH2B variants were significantly more frequent in familial glioma patients. Tumors withADAR orRNASEH2B variants recapitulated features of AGS, such as calcification and increased type I interferon expression. Patients carryingADAR orRNASEH2B variants showed upregulation of interferon-stimulated gene (ISG) transcripts in peripheral blood as seen in AGS. An increased ISG expression was also induced byADAR andRNASEH2B variants in tumor cells and was blocked by the JAK inhibitor Ruxolitinib. Our data implicate rare variants in the...
Source: Acta Neuropathologica - Category: Neurology Source Type: research