Population-based analysis of POT1 variants in a cutaneous melanoma case-control cohort.

Abstract

Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumour types, including melanoma, glioma, leukaemia and cardiac angiosarcoma. We sequenced all coding exons of the POT1 gene in 2928 European-descent melanoma cases and 3298 controls, identifying 43 protein-changing genetic variants. We performed POT1-telomere binding assays for all missense and stop-gained variants, finding nine variants that impair or disrupt protein-telomere complex formation, and we further define the role of variants in the regulation of telomere length and complex formation through molecular dynamics simulations. We determine that POT1 coding variants are a minor contributor to melanoma burden in the general population, with only about 0.5% of melanoma cases carrying germline pathogenic variants in this gene, but should be screened in individuals with a strong family history of melanoma and/or multiple malignancies.

• Authors: Irving Simonin-Wilmer, Raul Ossio, Emmett M Leddin, Mark Harland, Karen A Pooley, Mauricio Gerardo Martil de la Garza, Sofia Obolenski, James Hewinson, Chi C Wong, Vivek Iyer, John C Taylor, Julia A Newton-Bishop, D Timothy Bishop, Gerardo Andrés Cisneros, Mark M Iles, David J Adams, Carla Daniela Robles-Espinoza
• Journal: Journal of medical genetics (J Med Genet) Vol. 60 Issue 7 Pg. 692-696 (07 2023) ISSN: 1468-6244 [Electronic] England
• PMID: 36539277 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.

Chemical References

• Shelterin Complex
• Telomere-Binding Proteins
• POT1 protein, human

Topics

• Humans
• Melanoma (genetics)
• Skin Neoplasms (genetics)
• Shelterin Complex
• Telomere-Binding Proteins (genetics)
• Telomere (metabolism)
• Case-Control Studies
• Melanoma, Cutaneous Malignant