Introduction
Protection of Telomeres 1 (POT1) pathogenic variants confer melanoma predisposition, but surveillance guidelines are based on limited evidence from small case series (<20 patients) and limited to expert opinions. Larger studies are needed to characterize clinical patterns and establish evidence-based management strategies.
Methods
We conducted a retrospective study of 51 POT1 rare variant carriers from 39 families evaluated at the University of Michigan Cancer Genetics Clinic. Patients were referred due to their personal and/or family cancer history. Melanoma history, associated cancer history, and telomere length analysis were recorded. Telomere analysis was available for 28 patients. Patients were stratified by POT1 variant pathogenicity and telomere length. Variants were classified as pathogenic/likely pathogenic (P/LP, indicating high confidence of disease causation) or variants of uncertain significance (VUS, requiring additional evidence such as telomere analysis for clinical interpretation). Mann-Whitney U test was used to compare age at melanoma diagnosis between groups.
Results
21 patients had positive melanoma history (n=12 P/LP, n=9 VUS). Among POT1 patients with melanoma, median age at diagnosis was significantly earlier in confirmed P/LP carriers compared to VUS carriers (34.5 vs. 51.0, p=0.02). Multiple primary melanomas also occurred more frequently in confirmed P/LP carriers (66.7% vs. 44.4%). Of the 12 patients with multiple melanomas, 58.3% developed second primaries within two years. Commonly associated tumors and skin lesions in POT1 melanoma patients included dysplastic nevi (66.7%), basal cell carcinoma (23.8%), thyroid cancer (19.0%), breast cancer (19.0%), and squamous cell carcinoma (14.3%). Lastly, telomere analysis revealed higher melanoma rates in patients with lengths ≥90th percentile (n=20, 55%) compared to those with normal lengths (n=8, 12.5%), suggesting telomere length as an additional risk marker independent of variant classification.
Conclusions
POT1-associated melanoma demonstrates early onset, frequent multiple primaries, and high rates of comorbid skin lesions and tumors. These findings support the clinical utility of robust surveillance for P/LP carriers and those with long telomeres, including comprehensive, regular skin examinations. In light of long telomeres conferring higher cancer risk independent of variant classification, telomere length analysis may contribute to future gene-specific pathogenicity criteria and help reclassify select VUS carriers as pathogenic.
References
Robles-Espinoza CD, Harland M, Ramsay AJ, et al. POT1 loss-of-function variants predispose to familial melanoma. Nat Genet. 2014;46(5):478-481. doi:10.1038/ng.2947
Abu Shtaya A, Kedar I, Bazak L, et al. A POT1 Founder Variant Associated with Early Onset Recurrent Melanoma and Various Solid Malignancies. Genes (Basel). 2024;15(3):355. Published 2024 Mar 13. doi:10.3390/genes15030355
Accardo ML, Osborne J, Else T. POT1 Tumor Predisposition. 2020 Oct 29 [Updated 2025 Feb 13]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK563529/