Abstract
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.
Highlights
IntroductionHigh-grade gliomas in the pediatric population represent approximately 6.5% of all newly diagnosed childhood brain tumors[1]
High-grade gliomas in the pediatric population represent approximately 6.5% of all newly diagnosed childhood brain tumors[1].Similar to adults, prognosis remains poor with 5-year survival rates under 20%2
We describe the genetic evolution of a glioblastoma in a pediatric patient who underwent standard chemoradiation followed by recombinant poliovirus therapy as a part of his treatment regimen (Fig. 1)
Summary
High-grade gliomas in the pediatric population represent approximately 6.5% of all newly diagnosed childhood brain tumors[1]. Prognosis remains poor with 5-year survival rates under 20%2. Standard of care therapy is comprised of maximal safe surgical resection followed by adjuvant temozolomide and radiation therapy (RT), based on the Stupp protocol originally established in the adult setting[3]. Stromal Antigen-2 (STAG2) encodes a subunit within the cohesin complex, whose inactivation has been shown to cause aneuploidy through sister chromatid cohesion, and increased DNA damage that may promote further mutagenesis[5,6]. While STAG2 deficiency characterizes a small subset of glioblastoma, increasing preclinical evidence supports a driver role of this mutation in tumor formation and resistance to standard therapies in isogenic STAG2 deficient cell lines[7,8]
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