POT1 loss-of-function variants predispose to familial melanoma
Open accessAbstract
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.
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Melanoma-predisposing POT1 mutations reduce POT1 binding to single-stranded telomeric DNA.
“As a consequence, the ability of POT1 to bind to single-stranded telomeric DNA is diminished.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [62]
Carriers of POT1 mutations have longer telomeres, likely because POT1-mediated inhibition of telomerase is lost.
“Carriers of these mutations have longer telomeres, presumably owing to the loss of POT1-mediated inhibition of telomerase (BOX 1).”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [62]
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References 48 · Cited by 391
- Authors
- Robles-Espinoza, C. D., Harland, M., Ramsay, A. J., Aoude, L. G., Quesada, V., Ding, Z., Pooley, K. A., Pritchard, A. L., Tiffen, J. C., Petljak, M., Palmer, J. M., Symmons, J., Johansson, P., Stark, M. S., Gartside, M. G., Snowden, H., Montgomery, G. W., Martin, N. G., Liu, J. Z., Choi, J., Makowski, M., Brown, K. M., Dunning, A. M., Keane, T. M., López-Otín, C., Gruis, N. A., Hayward, N. K., Bishop, D. T., Newton-Bishop, J. A., & Adams, D. J.
- Affiliations
- University of Leeds (GB)
- Universidad de Oviedo (ES)
- QIMR Berghofer Medical Research Institute (AU)
- Wellcome Sanger Institute (GB)
- University of Cambridge (GB)
- National Cancer Institute (US)
- Leiden University (NL)
- Corresponding author
- Adams, David J
- ORCID
- Harland, Mark
- Aoude, Lauren G
- Ding, Zhihao
- Pooley, Karen A
- Pritchard, Antonia L
- Tiffen, Jessamy C
- Petljak, Mia
- Palmer, Jane M
- Johansson, Peter
- Stark, Mitchell S
- Montgomery, Grant W
- Martin, Nicholas G
- Liu, Jimmy Z
- Choi, Jiyeon
- Dunning, Alison M
- Keane, Thomas M
- Gruis, Nelleke A
- Hayward, Nicholas K
- Bishop, D Timothy
- Adams, David J
- Venue
- Nature Genetics
- Published
- 2014-03-30
- Volume
- 46
- Issue
- 5
- Pages
- 478-481
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC4266105
- OpenAlex
- W2070230289
- Cited by
- 391
- References
- 48
- Citations by year
- 2026: 21 · 2025: 17 · 2024: 34 · 2023: 28 · 2022: 29 · 2021: 26 · 2020: 43 · 2019: 27 · 2018: 33 · 2017: 32 · 2016: 44 · 2015: 41 · 2014: 16
- FWCI
- 29.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Apollo (University of Cambridge) (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Consultation of the Doctoral Thesis Database (TESEO) (Ministerio de Educación, Cultura y Deporte) (submittedVersion, cc-by-nc-nd)
- Funders
- Wellcome Trust (WT 098051, WT091310)
- Cancer Research UK (A10123, 13031, C588 ⁄A4994, 16565, (C8197/A10123), 10589, C588/A10589, C1287/A9540)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- POT1, familial melanoma, loss-of-function mutations, germline predisposition, telomere length, telomere binding, OB domain, mRNA splicing, multiple primary melanoma, melanoma susceptibility genes, co-segregation
- MeSH terms
- Shelterin Complex, Melanoma, Cutaneous Malignant, Cutaneous Malignant Melanoma, Amino Acid Sequence, Australia, Base Sequence, United Kingdom, Humans, Melanoma, Models, Molecular, Molecular Sequence Data, Netherlands, Pedigree, Protein Binding, Skin Neoplasms, Sequence Alignment, Telomere, Sequence Analysis, DNA, Genetic Predisposition to Disease, Reverse Transcriptase Polymerase Chain Reaction, Telomere-Binding Proteins
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