UK clinical practice guidelines for the management of patients with constitutional <i>POT1</i> pathogenic variants.

Abstract

Constitutional or germline pathogenic variants (GPVs) in <i>protection of telomeres 1 (POT1</i>) are associated with a variety of tumours resulting in the recognition of POT1-tumour predisposition syndrome (POT1-TPDS). These tumours may include cutaneous melanoma, angiosarcoma, haematological malignancy and brain tumours. Due to the rarity of <i>POT1</i> GPVs and limited available data, the overall lifetime cancer risks for individuals with POT1-TPDS are unclear. Furthermore, there is scant evidence to support the role of surveillance in early cancer detection in this patient group. A recent international publication suggested a surveillance protocol similar to that used in Li-Fraumeni Syndrome (LFS) could be offered to <i>POT1</i> pathogenic variant carriers, particularly where there are LFS-like features. However, current evidence for POT1-TPDS is not supportive of an equivalent lifetime cancer risk. Given the inclusion of <i>POT1</i> in the National Test Directory in England and the need for UK-based guidance, an expert group undertook a literature review to assess the phenotypic spectrum of POT1-TPDS and to provide lifetime risk estimates of <i>POT1</i>-associated cancers. The available evidence was shared with a small working group of experts that included clinical geneticists, dermatologists, sarcoma specialists, haematologists and radiologists to cover all aspects of the cancers most commonly associated with POT1-TPDS. Following structured expert group discussions, we achieved consensus on best practice recommendations for a POT1-TPDS UK management protocol.