Abstract

Abstract Cross-cancer profiling has shown that mutations in human DICER1 are recurrent in diverse cancers including intracranial sarcoma. Due to the rarity of these tumors, treatment options for these patients remain poorly defined. DICER1 encodes an endoribonuclease that processes the hairpin precursor microRNAs (miRNAs) into functionally mature miRNAs. In particular, hotspot mutations in the RNase IIIb domain of DICER1 are predicted to confer an oncogenic role although the precise mechanism is unknown. In a case of a 28-year-old male who presented with multicentric right frontal dural and parenchymal enhancing masses and underwent partial resection, pathology showed a DICER1-mutant primary intracranial sarcoma with a hotspot E1813G mutation in the RNase IIIb domain. Additionally, due to a family history of an unknown fatal brain tumor in his mother, the patient had additional molecular testing which revealed a germline BRCA2 mutation. After surgery, the patient received intensity-modulated radiation therapy followed by 6 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy with significant radiographic response and clinical improvement. He remains progression-free on radiological surveillance for 13 months since diagnosis. The treatment was well tolerated with clinically manageable myelosuppression (including grade 3 thrombocytopenia). This is the first reported case of an adult DICER1-mutant primary intracranial sarcoma patient with a germline BRCA2 mutation although the interaction between these oncogenic mechanisms is unclear. Based on the role of DICER1 in miRNA processing and to test the hypothesize that DICER1 mutations drive primary intracranial sarcoma through dysregulation of miRNA function, we have established a multi-institutional collaboration that is collecting and profiling DICER 1 mutant primary intracranial sarcoma cases from across the United States preliminary results of which will be presented. Identification of a miRNA-driven oncogenic mechanism in these tumors may yield novel targeted approaches beyond intensive chemotherapy for these patients.