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Similar to their adult counterparts, the prognosis for pediatric patients with high-grade gliomas remains poor. At time of recurrence, treatment options are limited and remain without consensus. This report describes the genetic findings, obtained from whole-exome sequencing of a pediatric patient with glioblastoma who underwent multiple surgical resections and treatment with standard chemoradiation, as well as a novel recombinant poliovirus vaccine therapy. Strikingly, despite the variety of treatments, there was persistence of a tumor clone, characterized by a deleterious  STAG2  mutation, whose deficiency in preclinical studies can cause aneuploidy and aberrant mitotic progression, but remains understudied in the clinical setting. There was near elimination of an  EGFR  mutated and amplified tumor clone after gross total resection, standard chemoradiation, and poliovirus therapy, followed by the emergence of a persistently  STAG2  mutated clone, with rare mutations in  PTPN11  and  BRAF , the latter composed of a novel deleterious mutation previously not reported in pediatric glioblastoma (p.D594G). This was accompanied by a mutation signature shift towards one characterized by increased DNA damage repair defects, consistent with the known underlying  STAG2  deficiency. As such, this case represents a novel report following the clinical and genetic progression of a  STAG2  mutated glioblastoma, including treatment with a novel and emerging immunotherapy. Although  STAG2  deficiency comprises only a small subset of gliomas, this case adds clinical evidence to existing preclinical data supporting a role for  STAG2  mutations in gliomagenesis and resistance to standard therapies.

Persistent STAG2 mutation despite multimodal therapy in recurrent pediatric glioblastoma