Journal
NATURE GENETICS
Volume 46, Issue 5, Pages 478-481Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2947
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Funding
- Consejo Nacional de Ciencia y Tecnologia of Mexico
- Cancer Research UK [C1287/A9540, C8197/A10123, C588/A4994, C588/A10589]
- Isaac Newton Trust
- National Health and Medical Research Council of Australia (NHMRC)
- Cure Cancer Australia
- NHMRC
- Cancer Council Queensland
- Dutch Cancer Society [UL 2012-5489]
- Genomics Initiative
- Spanish Ministry of Economy and Competitiveness through Instituto de Salud Carlos III (ISCIII)
- Consolider-Ingenio RNAREG Consortium
- Wellcome Trust [WT091310]
- Australia and New Zealand Banking Group Limited Trustees
- Red Tematica de Investigacion del Cancer (RTICC) del ISCIII
- Cancer Research UK [16565, 10589, 13031] Funding Source: researchfish
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Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases(l), and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease(2-5). 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.
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