(P 326) GERMLINE POT1 MUTATIONS IN ANGIOSARCOMA DIFFER FROM SOMATIC MUTATIONS

Objective: Protection of Telomeres Protein 1, (POT1) protein, is a component of the shelterin telomere complex, which is involved in regulating telomere length.
Genomic mutations in POT1 compromise chromosomal stability, leading to impaired cellular aging and apoptosis.
POT1 tumor predisposition syndrome (POT1-TPD) is caused by point mutations in POT1, with the POT1/R117C mutation being the most well-recognized.
This mutation results in abnormally long telomeres and is associated with an increased risk of familial cutaneous melanoma, angiosarcoma (AS), glioma
and chronic lymphocytic leukemia.
The prevalence of pathogenic POT1 mutations in AS ranges between 16-23%, although most patients do not exibit a POT1-TPD phenotype. In this study,
we aimed to examine the landscape of pathogenic POT1 gene mutations in angiosarcoma

Methods: Genomic profiles of clinical AS specimens analyzed by Foundation Medicine (Foundation Medicine, Inc., Cambridge, MA) between 2012-2018 were
retrieved using cBioPortal. A query for mutations in the POT1 gene identified 9/301 out of AS specimens (data sourced from MSKCC, Nat Commun 2022).
Clinical data for all patients harboring pathogenic POT1 variants were extracted

Results: Pathogenic POT1 mutations were identified in 3% (9/301) of AS patients. Among these, only one mutation (I78T) was a germline mutation associated with
familial melanoma, while the remaining eight were somatic splice-site mutations resulting in a truncated protein.
The primary tumor sites included skin in four patients and parotid gland, spleen, and pleura in one patient each. The median age of patients was 62 years
(range 46–81), and 7 of 9 patients were male. Co-mutations in TP53 were observed in 6/8 cases, while no significant associations with other genes were
noted. Somatic truncating mutations in POT1 were the predominant finding.

Conclusion: Our findings show that somatic POT1 mutations are predominantly truncating, resulting in POT1 loss, while germline POT1 mutations are typically point
mutations causing missense changes. We propose that germline truncating POT1 mutations are not compatible with life and, therefore, are not associated
with POT1-TPD. This observation should be validated in a larger AS cohort and may facilitate the identification of inherited cases of AS