Title |
POT1 loss-of-function variants predispose to familial melanoma
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Published in |
Nature Genetics, March 2014
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DOI | 10.1038/ng.2947 |
Pubmed ID | |
Authors |
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 |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 7 | 29% |
Australia | 3 | 13% |
United Kingdom | 2 | 8% |
Spain | 2 | 8% |
France | 2 | 8% |
Mexico | 1 | 4% |
Venezuela, Bolivarian Republic of | 1 | 4% |
Unknown | 6 | 25% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Scientists | 14 | 58% |
Members of the public | 9 | 38% |
Practitioners (doctors, other healthcare professionals) | 1 | 4% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 3 | 1% |
United States | 3 | 1% |
Netherlands | 1 | <1% |
Portugal | 1 | <1% |
Unknown | 268 | 97% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 69 | 25% |
Researcher | 57 | 21% |
Student > Master | 23 | 8% |
Student > Bachelor | 23 | 8% |
Student > Doctoral Student | 22 | 8% |
Other | 41 | 15% |
Unknown | 41 | 15% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 86 | 31% |
Biochemistry, Genetics and Molecular Biology | 81 | 29% |
Medicine and Dentistry | 39 | 14% |
Computer Science | 6 | 2% |
Immunology and Microbiology | 4 | 1% |
Other | 12 | 4% |
Unknown | 48 | 17% |