Population-based analysis of POT1 variants in a cutaneous melanoma case-control cohort
Simonin-Wilmer, I.; Ossio, R.; Leddin, E.; Harland, M.; Pooley, K. A.; Martil de la Garza, M. G.; Obolenski, S.; Hewinson, J.; Wong, C. C.; Iyer, V.; Taylor, J. C.; Newton-Bishop, J. A.; Bishop, D. T.; Cisneros, G. A.; Iles, M. M.; Adams, D. J.; Robles-Espinoza, C. D.
Show abstract
Pathogenic germline variants in the protection of telomeres 1 gene (POT1) have been associated with predisposition to a range of tumor types, including melanoma, glioma, leukemia and cardioangiosarcoma. We sequenced all coding exons of the POT1 gene in 2,929 European-descent melanoma cases and 3,298 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 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.
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