POT1 loss-of-function variants predispose to familial melanoma.

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

Journal: Nature genetics 2014;46(5):478-481

PMID: 24686849

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Abstract

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease. 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.

Address: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA. UK.; Section of Epidemiology and Biostatistics, Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, UK.; Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA) Universidad de Oviedo, Oviedo, Spain.; Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.; Molecular Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.; Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD, Australia.; Statistical Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA. UK.; Laboratory of Translational Genomics, National Cancer Institute, Bethesda, MD, USA.; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.; Leiden University Medical Centre, Leiden, The Netherlands.

DOI: 10.1038/ng.2947