Path-46. a novel pot1-tpd presentation: a germline pot1 mutation discovered in a patient with newly diagnosed posterior fossa ependymoma

Abstract INTRODUCTION POT1 tumor predisposition (POT1-TPD) is an autosomal dominant disorder characterized by increased lifetime malignancy risk. Melanoma, angiosarcoma and chronic lymphocytic leukemia are the most frequently reported malignancies. Other related cancers include gliomas. Protection of telomeres protein 1 is part of the shelterin protein complex to maintain/protect telomeres. Proposed mechanisms for oncogenesis with POT1 loss of function include telomere elongation and DNA damage response causing genomic instability. Ependymomas are a heterogeneous group comprising 12% of pediatric brain tumors and are locally aggressive with frequent recurrence. CASE PRESENTATION A healthy 3-year-old male presented with worsening vertigo, headaches, and emesis. Radiographic studies demonstrated a midline posterior fossa mass in the fourth ventricle. Following a gross total resection, pathology demonstrated a posterior fossa ependymoma, group A. Next generation sequencing (NGS) using our institution’s clinically validated panel, “CinCSeq”, demonstrated a POT1 splice site variant (c.1164-1G >A; variant allele frequency 46%). Paired germline testing via the molecular characterization initiative confirmed this variant as a heterozygote in the patient. Genetic testing confirmed a germline mutation in his mother who has a history of multiple nevi. He completed treatment with focal proton radiotherapy with no evidence of disease recurrence to date. DISCUSSION To our knowledge, this represents the first documented pediatric ependymoma with a familial, germline POT1 mutation. Somatic POT1 mutational frequency as determined by NGS in 60,000 solid tumors occurs at a rate of 2.94%. 45/60,000 were ependymomas with 1 non-benign POT1 mutation. Alterations of telomere maintenance have been reported in infratentorial ependymomas through increased human telomerase reverse transcriptase (hTERT) expression. This case sheds light on potential new mechanisms/predispositions for ependymoma development and the expanding phenotype of POT1-TPD. We recognize the POT1 mutation may have been discovered incidentally in this case. Further research into an association between POT1 and ependymomas is needed to advance our understanding.