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Loss-of-function variants in POT1 predispose to uveal melanoma
  1. Vaishnavi Nathan1,2,
  2. Jane M Palmer1,
  3. Peter A Johansson1,
  4. Hayley R Hamilton1,
  5. Sunil K Warrier3,
  6. William Glasson3,
  7. Lindsay A McGrath3,
  8. Vivian F S Kahl4,
  9. Raja S Vasireddy5,
  10. Hilda A Pickett4,
  11. Kelly M Brooks1,
  12. Antonia L Pritchard1,6,
  13. Nicholas K Hayward1
  1. 1 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  2. 2 Faculty of Medicine, University of Queensland, Brisbane, Queensland, Australia
  3. 3 Queensland Ocular Oncology Services, The Terrace Eye Centre, Brisbane, Queensland, Australia
  4. 4 Children's Medical Research Institute, University of Sydney, Westmead, New South Wales, Australia
  5. 5 Children's Hospital at Westmead, Sydney Children's Hospitals Network, Westmead, New South Wales, Australia
  6. 6 Division of Biomedical Sciences, University of the Highlands and Islands, Inverness, Scotland, UK
  1. Correspondence to Professor Nicholas K Hayward, Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Herston QLD 4006, Queensland, Australia; nicholas.hayward{at}

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Pathogenic germline variants in protection of telomeres 1 (POT1) result in a tumour predisposition syndrome (POT1-TPDS), which includes cutaneous melanoma (CM), glioma, chronic lymphocytic leukaemia (CLL), colorectal cancer, thyroid cancer and sarcoma.1 Through whole-genome sequencing (WGS) of 20 Australian individuals affected with both CM and uveal melanoma (UM), our study identified two truncating variants in POT1. Functional analyses assessing telomere length indicated longer telomeres in variant carriers, compared with healthy age-matched controls, similar to observations in CM patients with loss-of-function POT1 variants.2

The risk for development of cancers such as CM and UM is influenced by genetics. In UM, this has mainly been attributed to loss-of-function variants in BAP1.3 Predisposition in CM is largely due to multiple low-penetrance susceptibility alleles; however, 5%–12% of cases report first-degree or second-degree relatives with CM and in a proportion of these families disease segregates with high-penetrance single gene variants in CDKN2A, CDK4 and the telomere maintenance genes POT1, ACD, TERF2IP and TERT (reviewed in ref 4). Pathogenic germline variants in POT1 result in an increase in telomere length and susceptibility to many cancer types including CM, glioma, CLL, thyroid cancer, colorectal cancer, angiosarcoma1 and osteosarcoma,5 now termed the POT1-TPDS. There is also recent evidence to suggest histological differences in melanomas of POT1 variant carriers versus non-carriers, highlighting the importance of telomere dysfunction on tumour biology.6 POT1 binds to telomeric single-stranded DNA (ssDNA) overhangs, preventing telomerase accessibility. Highly conserved oligonucleotide/oligosaccharide-binding (OB) folds in POT1 are essential for specific binding to ssDNA, and loss of function of these OB domains leads to increased telomere elongation due to an inability to inhibit telomerase. Certain germline missense variants occurring in these OB domains, and other protein truncating variants, have been reported to disrupt POT1 function, leading to …

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  • Contributors VN designed the research study, prepared samples, conducted experiments, analysed data and prepared the manuscript. JMP recruited patients, consented patients, collected samples, acquired data and prepared the manuscript. PAJ designed the research study, analysed data and prepared the manuscript. HRH acquired data and prepared the manuscript. SKW, WG and LAM recruited patients and prepared the manuscript. VFSK, RSV and HAP conducted experiments, analysed data and prepared the manuscript. KMB prepared samples, supervised the project and prepared the manuscript. ALP designed the research study, supervised the project and prepared the manuscript. NKH provided funding for the study, designed the research study, supervised the project and prepared the manuscript.

  • Funding All authors reviewed the manuscript and provided feedback. The study and NKH is funded by the National Health and Medical Research Council (NHMRC; 1093017, 1117663), ALP is funded by Highland Island Enterprise (HMS 9353763), KMB is funded by Cure Cancer Australia. VN is supported by an Australian Government Research Training Programme Scholarship.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval Participants were consented for this study under ethics approval granted by the QIMR Berghofer Medical Research Institute Human Research Ethics Committee (HREC; reference number: HREC/14/QPAH/495).

  • Provenance and peer review Not commissioned; externally peer reviewed.