Association of the POT1 Germline Missense Variant p.I78T With Familial Melanoma

Kim Wong, Carla Daniela Robles-Espinoza, David Rodríguez, Saskia S. Rudat, Susana Puig, Miriam Potrony Mateu, Chi C. Wong, James Hewinson, Paula Aguilera, Joan Anton Puig-Butille, Brigitte Bressac-de Paillerets, Hélène Zattara, Louise van der Weyden, Christopher D M Fletcher, Thomas Brenn, Mark Arends, Victor Quesada, Julia Newton-Bishop, Carlos Lopez-Otin, D Timothy BishopPaul W. Harms, Timothy M. Johnson, Alison B. Durham, David B. Lombard, David J Adams

Research output: Contribution to journalArticlepeer-review


Importance: Protection of Telomeres 1 (POT1) is a critical component of the shelterin complex, a multi-protein machine that regulates telomere length and protects telomere ends. Germline mutations of POT1 have been linked to familial melanoma, and somatic mutations are associated with a range of malignancies including cutaneous T-cell lymphoma (CTCL). Objective: To characterise pathogenic variation in POT1 to inform clinical management. Design: Analysis of a melanoma pedigree revealed a novel germline POT1 variant (p.I78T, c.233T>C, chromosome 7, g.124870933A>G, GRCh38) which was subsequently found in a further two pedigrees. Setting: Familial melanoma/dermatological cancer clinic. Participants: Melanoma prone individuals/families. Main Outcomes and Measures: The POT1 p.I78T variant was identified. Clinical features and characteristics of patients with this mutation were reported. A pedigree analysis, genome-wide SNP genotyping of germline DNA, and a somatic genetic analysis on available nevi and a melanoma were performed. Results: The POT1 p.I78T variant was found in multiple melanoma pedigrees, all of whom were of self-reported Jewish descent, and was shown to disrupt POT1-telomere binding. We report that a UV signature is associated with nevus and melanoma formation in POT1 variant carriers, and that somatic mutations in driver genes such as BRAF, NRAS and KIT contribute to disease evolution. Conclusions and Relevance: POT1 p.I78T is a newly identified likely pathogenic variant meriting screening for in melanoma families after more common predisposition genes such as CDKN2A have been excluded, or included as part of gene panel testing
Original languageEnglish
JournalJAMA Dermatology
Publication statusPublished - 26 Dec 2018


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