Familial Cancer

, Volume 14, Issue 4, pp 621–628 | Cite as

POLE mutations in families predisposed to cutaneous melanoma

  • Lauren G. AoudeEmail author
  • Ellen Heitzer
  • Peter Johansson
  • Michael Gartside
  • Karin Wadt
  • Antonia L. Pritchard
  • Jane M. Palmer
  • Judith Symmons
  • Anne-Marie Gerdes
  • Grant W. Montgomery
  • Nicholas G. Martin
  • Ian Tomlinson
  • Stephen Kearsey
  • Nicholas K. Hayward
Original Article


Germline mutations in the exonuclease domain of POLE have been shown to predispose to colorectal cancers and adenomas. POLE is an enzyme involved in DNA repair and chromosomal DNA replication. In order to assess whether such mutations might also predispose to cutaneous melanoma, we interrogated whole-genome and exome data from probands of 34 melanoma families lacking pathogenic mutations in known high penetrance melanoma susceptibility genes: CDKN2A, CDK4, BAP1, TERT, POT1, ACD and TERF2IP. We found a novel germline mutation, POLE p.(Trp347Cys), in a 7-case cutaneous melanoma family. Functional assays in S. pombe showed that this mutation led to an increased DNA mutation rate comparable to that seen with a Pol ε mutant with no exonuclease activity. We then performed targeted sequencing of POLE in 1243 cutaneous melanoma cases and found that a further ten probands had novel or rare variants in the exonuclease domain of POLE. Although this frequency is not significantly higher than that in unselected Caucasian controls, we observed multiple cancer types in the melanoma families, suggesting that some germline POLE mutations may predispose to a broad spectrum of cancers, including melanoma. In addition, we found the first mutation outside the exonuclease domain, p.(Gln520Arg), in a family with an extensive history of colorectal cancer.


Cutaneous melanoma POLE Germline mutation 



The authors would like to thank all the participants of this study. This project was funded by the National Health and Medical Research Council of Australia (NHMRC), the Genomic Medicine and Cancer Themes of the Oxford NIHR Comprehensive Biomedical Research Centre, the Oxford Experimental Cancer Medicine Centre, Cancer Research UK Programme Grant (to IT), and core funding to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/09/Z). LGA was supported by an Australia and New Zealand Banking Group Limited Trustees Ph.D. scholarship. NKH and GWM are supported by fellowships from the NHMRC. Work in SEK’s group is supported by a MRC Grant MR/L016591/1. ALP is supported by Cure Cancer Australia and Rio Tinto Ride to Conquer Cancer.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10689_2015_9826_MOESM1_ESM.docx (995 kb)
Supplementary material 1 (DOCX 996 kb)


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Copyright information

© Springer Science+Business Media Dordrecht 2015

Authors and Affiliations

  • Lauren G. Aoude
    • 1
    Email author
  • Ellen Heitzer
    • 2
  • Peter Johansson
    • 1
  • Michael Gartside
    • 1
  • Karin Wadt
    • 4
  • Antonia L. Pritchard
    • 1
  • Jane M. Palmer
    • 1
  • Judith Symmons
    • 1
  • Anne-Marie Gerdes
    • 4
  • Grant W. Montgomery
    • 1
  • Nicholas G. Martin
    • 1
  • Ian Tomlinson
    • 5
  • Stephen Kearsey
    • 3
  • Nicholas K. Hayward
    • 1
  1. 1.QIMR Berghofer Medical Research InstituteBrisbaneAustralia
  2. 2.Institut für HumangenetikMedizinische Universität GrazGrazAustria
  3. 3.Department of ZoologyUniversity of OxfordOxfordUK
  4. 4.Department of Clinical GeneticsRigshospitaletCopenhagenDenmark
  5. 5.Molecular and Population Genetics Laboratory and Genomic Medicine Theme Oxford NIHR Biomedical Research Centre, Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUK

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