Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, and rare variants in CDK4, BRCA2, BAP1 and the promoter of TERT have also been linked to the disease2,3,4,5. 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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We thank the UK10K Consortium (funded by the Wellcome Trust; WT091310) for access to control data. D.J.A., C.D.R.-E., Z.D., J.Z.L., J.C.T., M.P. and T.M.K. were supported by Cancer Research UK and the Wellcome Trust (WT098051). C.D.R.-E. was also supported by the Consejo Nacional de Ciencia y Tecnología of Mexico. K.A.P. and A.M.D. were supported by Cancer Research UK (grants C1287/A9540 and C8197/A10123) and by the Isaac Newton Trust. N.K.H. was supported by a fellowship from the National Health and Medical Research Council of Australia (NHMRC). L.G.A. was supported by an Australia and New Zealand Banking Group Limited Trustees PhD scholarship. A.L.P. is supported by Cure Cancer Australia. The work was funded in part by the NHMRC and Cancer Council Queensland. The work of N.A.G. was in part supported by the Dutch Cancer Society (UL 2012-5489). M.H., J.A.N.-B. and D.T.B. were supported by Cancer Research UK (programme awards C588/A4994 and C588/A10589 and the Genomics Initiative). C.L.-O., A.J.R. and V.Q. are funded by the Spanish Ministry of Economy and Competitiveness through the Instituto de Salud Carlos III (ISCIII), the Red Temática de Investigación del Cáncer (RTICC) del ISCIII and the Consolider-Ingenio RNAREG Consortium. C.L.-O. is an investigator with the Botín Foundation.

Author information

Author notes

    • Carla Daniela Robles-Espinoza
    • , Mark Harland
    • , Andrew J Ramsay
    •  & Lauren G Aoude

    These authors contributed equally to this work.

    • Nicholas K Hayward
    • , D Timothy Bishop
    • , Julia A Newton-Bishop
    •  & David J Adams

    These authors jointly directed this work.


  1. Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.

    • Carla Daniela Robles-Espinoza
    • , Zhihao Ding
    • , Jessamy C Tiffen
    • , Mia Petljak
    • , Thomas M Keane
    •  & David J Adams
  2. Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.

    • Mark Harland
    • , Helen Snowden
    • , D Timothy Bishop
    •  & Julia A Newton-Bishop
  3. Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.

    • Andrew J Ramsay
    • , Víctor Quesada
    •  & Carlos López-Otín
  4. Oncogenomics Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.

    • Lauren G Aoude
    • , Antonia L Pritchard
    • , Jane M Palmer
    • , Judith Symmons
    • , Peter Johansson
    • , Mitchell S Stark
    • , Michael G Gartside
    •  & Nicholas K Hayward
  5. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Karen A Pooley
  6. Molecular Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.

    • Grant W Montgomery
  7. Genetic Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia.

    • Nicholas G Martin
  8. Statistical Genetics, Wellcome Trust Sanger Institute, Hinxton, UK.

    • Jimmy Z Liu
  9. Laboratory of Translational Genomics, National Cancer Institute, Bethesda, Maryland, USA.

    • Jiyeon Choi
    • , Matthew Makowski
    •  & Kevin M Brown
  10. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

    • Alison M Dunning
  11. Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

    • Nelleke A Gruis


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C.D.R.-E., M.H., J.A.N.-B., D.T.B., N.K.H. and D.J.A. designed the study and wrote the manuscript. C.D.R.-E., M.H., L.G.A., J.C.T., M.M., J.C., M.P., A.J.R., Z.D., V.Q., A.L.P., J.M.P., J.S., M.S.S., N.G.M., M.G.G., A.M.D., K.A.P., P.J., J.Z.L., K.M.B., C.L.-O. and T.M.K. performed experiments or analysis. N.A.G., G.W.M., H.S. and N.G.M. provided vital biological resources.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to David J Adams.

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    Supplementary Figures 1–8, Supplementary Tables 1, 2 and 4–8 and Supplementary Note

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    Supplementary Table 3

    Genes with cosegregating variants from the 28 pedigrees for which we had sequence data for 3 or more members and their GO terms.

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