Supplementary Material for: Malignant progression of SEGA-imitating fibrous meningioma in a child carrying a germline CHEK2 mutation

Background: The subependymal giant cell astrocytoma (SEGA) predominantly occurs in patients with tuberous sclerosis. Here, we present an unusual aggressive transformation of SEGA-imitating fibrous meningioma in a child carrying a germline CHEK2 mutation Methods: This case study was conducted at a tertiary pediatric oncology center in accordance with current diagnostic and therapeutic standards. Tumor classification followed WHO CNS5 criteria and was complemented by genome-wide DNA methylation profiling. Comprehensive molecular workup included germline and somatic whole-exome sequencing, copy-number analysis, and RNA-sequencing; Results: An 8.5-year-old girl presented with an intraventricular tumor initially diagnosed as SEGA based on imaging and partial resection histology. Treatment with an mTOR inhibitor led to four years of stability before rapid progression and death due to postoperative brain edema. Re-examination of both specimens revealed transformation into an aggressive anaplastic meningioma, while the initial lesion was reclassified as fibrous meningioma. Whole-exome and microarray analyses excluded germline TSC1/TSC2 defects but identified a pathogenic germline CHEK2 variant (c.1466del, p.Asn489ThrfsTer23). Somatic alterations involving NF1, and TP53 were found in the primary tumor. Conclusions: Constitutional CHEK2 mutations combined with somatic NF1 defect may have promoted the malignant progression of SEGA-imitating fibrous meningioma and its favorable initial response to mTOR inhibitors.