Germline POT1 Variants: A Critical Perspective on POT1 Tumor Predisposition Syndrome

Abstract

The Protection of Telomere 1 (POT1) gene was identified as a melanoma predisposition candidate nearly 10 years ago. Thereafter, various cancers have been proposed as associated with germline POT1 variants in the context of the so-called POT1 Predisposition Tumor Syndrome (POT1-TPD). While the key role, and related risks, of the alterations in POT1 in melanoma are established, the correlation between germline POT1 variants and the susceptibility to other cancers partially lacks evidence, due also to the rarity of POT1-TPD. Issues range from the absence of functional or segregation studies to biased datasets or the need for a revised classification of variants. Furthermore, a proposal of a surveillance protocol related to the cancers associated with POT1 pathogenic variants requires reliable data to avoid an excessive, possibly unjustified, burden for POT1 variant carriers. We propose a critical perspective regarding data published over the last 10 years that correlate POT1 variants to various types of cancer, other than cutaneous melanoma, to offer food for thought for the specialists who manage cancer predisposition syndromes and to stimulate a debate on the grey areas that have been exposed.

Keywords: POT1; cancer predisposition; germline; melanoma; pathogenic variants; telomeres.

Figure 1

On the left, the main functions in which the protein Protection of Telomere 1 is involved. On the right, a summary of the main cancers proposed as associated with POT1 Tumor Predisposition Syndrome. Cutaneous melanoma is at the top of the pyramid for the consistency of the data supporting its association with the syndrome (created with BioRender.com).