POT1 genetic testing in melanoma-prone families in Sweden: germline variant prevalence and tumor spectrum in identified carriers

Authors

  • Konstantinos Papadakis Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden https://orcid.org/0009-0009-1039-2873
  • Francesca Portelli Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden https://orcid.org/0000-0002-3325-2357
  • Karina Schultz Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; Theme Cancer, Karolinska University Hospital, Stockholm, Sweden https://orcid.org/0000-0003-4086-1289
  • Hedvig Olsson Sterky Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
  • Ismini Vassilaki Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; Department of Clinical Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden.
  • Jan Lapins Dermatology and Venereology Unit, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden; Department of Dermatology, Karolinska University Hospital, Stockholm, Sweden https://orcid.org/0000-0002-0882-8959
  • Michael R. Sargen Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, USA https://orcid.org/0000-0003-1039-2522
  • Sofia Obolenski Experimental Cancer Genetics, Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK; Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands https://orcid.org/0000-0002-6709-7332
  • David J. Adams Experimental Cancer Genetics, Wellcome Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK https://orcid.org/0000-0001-9490-0306
  • Muyi Yang Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden
  • Veronica Höiom Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; Theme Cancer, Karolinska University Hospital, Stockholm, Sweden https://orcid.org/0000-0002-3957-5667
  • Hildur Helgadottir Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden; Theme Cancer, Karolinska University Hospital, Stockholm, Sweden https://orcid.org/0000-0002-0735-4771

DOI:

https://doi.org/10.2340/1651-226X.2025.44048

Keywords:

POT1, cutaneous melanoma, sarcoma, cancer, telomere, mutation

Abstract

Background and purpose: Approximately 5–10% of cutaneous melanoma occurs in individuals with a family history of the disease. While known high-penetrance genes, such as CDKN2A, explain some cases, a substantial proportion of hereditary melanoma remains genetically undefined. Recently, germline variants in genes involved in telomere regulation, including POT1, TERT, ACD, and TERF2IP, have been identified in melanoma-prone families. This study investigated the prevalence and pathogenicity of POT1 variants in a Swedish familial melanoma cohort.

Patient/material and methods: A total of 168 familial melanoma cases were screened for CDKN2A, CDK4, BAP1, and POT1. The population frequency of pathogenic variants (PVs) was assessed using the SweGen and the gnomAD databases. Functional evaluation was performed using a saturation genome editing (SGE) assay. Telomere length analysis was performed using quantitative polymerase chain reaction (qPCR) on blood-derived DNA from melanoma patients and healthy controls. The melanomas of the carriers were reviewed by expert dermatopathologists.

Results: Among the 161 CDKN2A/CDK4/BAP1-negative melanoma families included in this cohort, only one likely PV in POT1 (c.676C > A, p.His226Asn) was identified (0.6%). Population data confirmed its rarity. The carrier family exhibited multiple early-onset melanomas, with two out of three invasive cases displaying spitzoid morphology, and several other tumors. No significant telomere length differences were observed between carriers and controls. Two additional POT1 variants of uncertain significance were detected; both were predicted to be benign.

Interpretation: POT1 PVs were rare in the studied Swedish familial melanoma cases, implying limited contribution to hereditary melanoma in this population. Nonetheless, the identification of a previously unknown likely PV further supports the need for continued genetic screening in selected cases. POT1 testing should be considered in families with multiple melanomas, early onset and spitzoid histopathology, and co-occurring with other syndromic tumors.

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Published

2025-08-25

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Papadakis, K., Portelli, F., Schultz, K., Olsson Sterky, H., Vassilaki, I., Lapins, J., … Helgadottir, H. (2025). POT1 genetic testing in melanoma-prone families in Sweden: germline variant prevalence and tumor spectrum in identified carriers. Acta Oncologica, 64, 1102–1108. https://doi.org/10.2340/1651-226X.2025.44048

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Vol. 64 (2025): Acta Oncologica

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Copyright (c) 2025 Konstantinos Papadakis, Francesca Portelli, Karina Schultz, Hedvig Olsson Sterky, Ismini Vassilaki, Jan Lapins, Michael R. Sargen, Sofia Obolenski, David J. Adams, Muyi Yang, Veronica Höiom, Hildur Helgadottir

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