ID #506 Genetic Insights into Pediatric Low-Grade Gliomas: A Case of Pilocytic Astrocytoma with Germline Mutations in POT1 and BRIP1

Abstract

The prevalence of pediatric cancer attributable to genetic predisposition is growing, the largest percentage belonging to children with central nervous system neoplasms. Low-grade glioma is the most common brain tumor in children of which Neurofibromatosis Type I is a known predisposition. Identification of a cancer predisposition syndrome can influence treatment decisions, allow for initiation of surveillance and lead to identification of at increased risk family members.

A previously healthy 7-year-old female presented with acute onset severe headache and persistent emesis. CT Head without contrast demonstrated a left-sided cerebellar mass with cystic and solid components and obstructive hydrocephalus. Following gross total resection, pathology demonstrated a WHO Grade I KIAA1549::BRAF driven pilocytic astrocytoma. Paired germline testing via the Molecular Characterization Initiative identified a likely pathogenic frameshift variant in POT1 (c.1875_18757delinsGG, VAF 33%) and a likely pathogenic BRIP1 slice site variant (c. 206-1G>T, VAF 54%). Both variants are predicted to result in loss of function of the gene. POT1 is a gene that protects cells from inappropriate DNA damage and plays a critical role in telomere regulation. Pathogenic variants confer an increased risk of certain tumors including cutaneous melanoma, chronic lymphocytic leukemia (CLL), angiosarcoma, oligodendroglioma and high grade glioma[1]. BRIP1 is a gene involved in DNA repair and when mutated, increases risk of certain malignancies, most notably ovarian and fallopian tube cancer and more recently familial glioma[2]. Interestingly, the child’s mother had bilateral salpingo oophorectomy for treatment of endometriosis prior to the age of 40. The maternal pedigree is also notable for CLL and metastatic melanoma. To our knowledge, this represents the first documented pediatric low grade glioma patient with cooccurring germline POT1 and BRIP1 mutations. Molecular markers not only enhance our understanding of tumor biology but also play a critical role in advancing knowledge of cancer predisposition syndromes.

1. Baptista Freitas, M., Desmyter, L., Badoer, C. et al. POT1 tumour predisposition: a broader spectrum of associated malignancies and proposal for additional screening program. Eur J Hum Genet 32, 980–986 (2024). https://doi.org/10.1038/s41431-024-01611-0

2. Dong-Joo Choi et al. The genomic landscape of familial glioma. Sci Adv. 2023 Apr 28;9(17):eade2675. doi: 10.1126/sciadv.ade2675. Epub 2023 Apr 28. PMID: 37115922; PMCID: PMC10146888.