POT1 loss-of-function variants predispose to familial melanoma

Robles-Espinoza, Carla Daniela, Harland, Mark, Ramsay, Andrew J, Aoude, Lauren G, Quesada, Víctor, Ding, Zhihao, Pooley, Karen A, Pritchard, Antonia L, Tiffen, Jessamy C, Petljak, Mia, Palmer, Jane M, Symmons, Judith, Johansson, Peter, Stark, Mitchell S., Gartside, Michael G, Snowden, Helen, Montgomery, Grant W, Martin, Nicholas G, Liu, Jimmy Z, Choi, Jiyeon, Makowski, Matthew, Brown, Kevin M, Dunning, Alison M, Keane, Thomas M, Lopez-Otin, Carlos, Gruis, Nelleke A, Hayward, Nicholas K, Bishop, D Timothy, Newton-Bishop, Julia A and Adams, David J (2014) POT1 loss-of-function variants predispose to familial melanoma. Nature Genetics, 46 5: 478-481. doi:10.1038/ng.2947

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Author Robles-Espinoza, Carla Daniela
Harland, Mark
Ramsay, Andrew J
Aoude, Lauren G
Quesada, Víctor
Ding, Zhihao
Pooley, Karen A
Pritchard, Antonia L
Tiffen, Jessamy C
Petljak, Mia
Palmer, Jane M
Symmons, Judith
Johansson, Peter
Stark, Mitchell S.
Gartside, Michael G
Snowden, Helen
Montgomery, Grant W
Martin, Nicholas G
Liu, Jimmy Z
Choi, Jiyeon
Makowski, Matthew
Brown, Kevin M
Dunning, Alison M
Keane, Thomas M
Lopez-Otin, Carlos
Gruis, Nelleke A
Hayward, Nicholas K
Bishop, D Timothy
Newton-Bishop, Julia A
Adams, David J
Title POT1 loss-of-function variants predispose to familial melanoma
Formatted title
POT1 loss-of-function variants predispose to familial melanoma
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1546-1718
Publication date 2014
Sub-type Article (original research)
DOI 10.1038/ng.2947
Volume 46
Issue 5
Start page 478
End page 481
Total pages 4
Place of publication New York United States
Publisher Nature Publishing Group
Collection year 2015
Language eng
Subject 1311 Genetics
Formatted 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 69 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 74 times in Scopus Article | Citations
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