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.

为了寻找新的易患肿瘤特别是神经胶质瘤的种系改变，我们研究了一个有两个兄弟的家庭，他们的两个兄弟都受到间变性神经胶质瘤的影响，他们的父亲和父亲的叔叔被诊断出患有前列腺癌。在这个家族中，全外显子组测序在Aicardi–Goutières综合征（AGS）基因ADAR和RNASEH2B与肿瘤表型共分离的同时产生罕见的杂合变体。AGS是一种遗传诱发的炎症性疾病，尤其是大脑的炎症性疾病，迄今为止尚未与持续增加的癌症风险相关。通过定向测序，我们确定了新颖的ADAR和RNASEH2B变体，以及AGS突变ADAR的频率增加了3到17倍，c.577C> G; p。（P193A）和RNASEH2B， c.529G> A; p。（A177T）在家族性神经胶质瘤患者的生殖系以及胶质母细胞瘤和前列腺癌的测试和验证队列中，与种族相匹配的对照组进行比较，因此，罕见的RNASEH2B变异在家族性神经胶质瘤患者中更为常见。具有ADAR或RNASEH2B变体的肿瘤概括了AGS的特征，例如钙化和I型干扰素表达增加。携带ADAR或RNASEH2B变体的患者显示出外周血中干扰素刺激基因（ISG）转录本的上调，如AGS所示。IDAR表达也由ADAR诱导，并且RNASEH2B变体在肿瘤细胞中，并被JAK抑制剂Ruxolitinib阻断。我们的数据暗示了AGS基因ADAR和RNASEH2B中的稀有变异以及神经胶质瘤和前列腺癌风险和肿瘤发生中的I型干扰素签名，这与神经胶质瘤和前列腺癌发展中炎症驱动的恶性转化的遗传基础一致。