A novel POT1-TPD presentation: A germline pathogenic POT1 variant discovered in a patient with newly diagnosed posterior fossa ependymoma

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 [1]. Protection of telomeres protein 1 (POT1) is part of the shelterin protein complex to maintain/protect telomeres [2]. Proposed mechanisms for oncogenesis with POT1 loss of function include telomere elongation and DNA damage response causing genomic instability [3]. Ependymomas are a heterogeneous group representing one-third of pediatric brain tumors and are locally aggressive with frequent recurrence [4].

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," identified a POT1 splice site variant (c.1164-1G>A; variant allele fraction 46 %). Paired germline testing via the Molecular Characterization Initiative confirmed this variant as heterozygous in the patient. Genetic testing confirmed the POT1 pathogenic variant in his mother, who has a history of multiple nevi. The patient completed treatment with focal proton radiotherapy with no evidence of disease recurrence to date.

To our knowledge, this represents the first documented pediatric ependymoma patient with a familial, germline POT1 pathogenic variant. Somatic POT1 mutational frequency, as determined by NGS in over 60,000 solid tumors, is 2.94 %. Among this cohort, 48 cases were ependymomas with one non-benign POT1 mutation [5]. Alterations of telomere maintenance have been reported in intracranial ependymomas previously through increased human telomerase reverse transcriptase (hTERT) expression [6,7]. This case sheds light on a potential new predisposition for ependymoma development and the expanding phenotype of POT1-TPD. We recognize the POT1 pathogenic variant may have been discovered incidentally in this case. Further research is needed to advance our understanding of the association between POT1 genetic alterations and ependymomas.