POT1 tumor predisposition: a broader spectrum of associated malignancies and proposal for additional screening program

Abstract Protection of Telomeres Protein 1 protein is an essential subunit of the shelterin telomere binding complex, regulating telomere length. Some POT1 gene pathogenic variants lead to telomere elongation and consequently genomic instability, which predisposes to a higher risk of cancer. POT1 tumour predisposition (POT1-TPD) is inherited in an autosomal dominant manner and it is related to an increased lifetime risk for cutaneous melanoma, chronic lymphocytic leukaemia (CLL), angiosarcoma (mostly cardiac angiosarcomas) and gliomas. In this work, we aim to describe a broader cancer phenotype related to POT1 tumour predisposition, in three different families. We performed genetic tests in 3 index cases identifying 3 different POT1 pathogenic variants: NC_000007.14(NM_015450.2):c.349C > T; NC_000007.14(NM_015450.2):c.233T > C and NC_000007.14(NM_015450.2):c.818G > A; already described in the literature. In total, thirty-four family relatives were tested and eighteen were positive. In these three families, it was possible to observe the typical POT1-TPD (cutaneous melanoma, cardiac angiosarcoma, chronic lymphocytic leukaemia and brain tumours). Nonetheless, these families present a higher incidence of other types of cancers: bone and soft tissue sarcomas, lung cancer, papillary thyroid cancer, early onset prostate cancer and leukaemia in association with POT1 pathogenic variants. These findings are important to better understand the implications of POT1 pathogenic variants, their prevalence, their penetrance and better characterize them. Furthermore, it can play an important role in future discussions about POT1 mutation screening criteria, improving genetic counselling of these patients and their families and also help to developed more accurate surveillance protocols for POT1 carriers.