POT1 loss-of-function variants predispose to familial melanoma

Carla Daniela Robles-Espinoza, Mark Harland, Andrew J. Ramsay, Lauren G. Aoude, Victor Quesada, Zhihao Ding, Karen A. Pooley, Antonia L. Pritchard, Jessamy C. Tiffen, Mia Petljak, Jane M. Palmer, Judith Symmons, Peter A. Johansson, Mitchell S. Stark, Michael G. Gartside, Helen Snowden, Grant W. Montgomery, Nicholas G. Martin, Jimmy Z. Lite, Jiyeon ChoiMatthew Makowski, Kevin M. Brown, Alison M. Dunning, Thomas M. Keane, Carlos Lopez-Otin, Nelleke A. Gruis, Nicholas K. Hayward, D. Timothy Bishop, Julia A. Newton-Bishop, David J. Adams

Research output: Contribution to journalArticlepeer-review

293 Citations (Scopus)


Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease2,3,4,5. Here we set out to identify new high-penetrance susceptibility genes by sequencing 184 melanoma cases from 105 pedigrees recruited in the UK, The Netherlands and Australia that were negative for variants in known predisposition genes. We identified families where melanoma cosegregates with loss-of-function variants in the protection of telomeres 1 gene (POT1), with a proportion of family members presenting with an early age of onset and multiple primary tumors. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding and leading to increased telomere length. These findings suggest that POT1 variants predispose to melanoma formation via a direct effect on telomeres.
Original languageEnglish
Pages (from-to)478-481
Number of pages4
JournalNature Genetics
Issue number5
Early online date30 Mar 2014
Publication statusPublished - May 2014


  • 3ref2021


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