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POT1 and multiple primary melanomas: the dermatological phenotype
  1. Ellie J Maas1,
  2. Emily DeBortoli1,
  3. Vaishnavi Nathan1,
  4. Ned P Freeman2,
  5. Adam Mothershaw1,
  6. Darren J Smit1,
  7. Brigid Betz-Stablein1,
  8. Lauren G Aoude3,
  9. Mitchell S Stark1,
  10. Richard A Sturm1,
  11. H Peter Soyer1,4,
  12. Aideen M McInerney-Leo1
  1. 1Frazer Institute, The University of Queensland, Dermatology Research Centre, Brisbane, Queensland, Australia
  2. 2Royal Brisbane and Women's Hospital, Herston, Queensland, Australia
  3. 3Frazer Institute, The University of Queensland, Surgical Oncology Group, Brisbane, Queensland, Australia
  4. 4Department of Dermatology, Princess Alexandra Hospital, Brisbane, Queensland, Australia
  1. Correspondence to A/Prof Aideen M McInerney-Leo, Integrating Genomics into Medicine, Frazer Institute, University of Queensland, Brisbane, QLD, Australia; a.mcinerney{at}


POT1 is the second most frequently reported gene (after CDKN2A) in familial melanoma. Pathogenic variants are associated with earlier onset and/or multiple primary melanomas (MPMs). To date, POT1 phenotypical reports have been largely restricted to associated malignancies, and description of the dermatological landscape has been limited. We identified 10 variants in n=18 of 384 (4.7%) unrelated individuals (n=13 MPMs; n=5 single primary melanomas) of European ancestry. Five variants were rare (minor allele frequency <0.001) or novel (two loss-of-function (LOF), one splice acceptor and two missense) and were predicted to be functionally significant, in five unrelated probands with MPMs (≥3 melanomas). We performed three-dimensional total body photography on both individuals with confirmed pathogenic LOF variants to characterise the dermatological phenotype. Total body naevus counts (≥2 mm diameter) were significantly higher (p=7.72×10–12) in carriers compared with a control population. Majority of naevi were on the probands’ back and lower limb regions, where only mild to moderate ultraviolet (UV) damage was observed. Conversely, the head/neck region, where both probands exhibited severe UV damage, had comparably fewer naevi. We hypothesise that carriage of functionally significant POT1 variants is associated with increased naevus counts generally, and naevi >5 mm in diameter specifically and the location of these are independent of UV damage.

  • Whole Exome Sequencing
  • Genetic Research
  • Genotype
  • Phenotype

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  • Contributors EM wrote the paper (80%), edited the manuscript (30%), and analysed imaging data (80%) and WES data (70%). ED assembled figures (100%) and edited the manuscript (10%). VN edited the manuscript (10%). NPF wrote the paper (5%) and edited the manuscript (5%). AM did the bioinformatic processing of imaging data (100%) and edited the manuscript (5%). DJS did the bioinformatic processing of samples (100%) and edited the manuscript (5%). BB-S edited the manuscript (5%) and analysed imaging data (15%). LGA edited the manuscript (5%). MSS edited the manuscript (5%) and obtained ethics approval. RS edited the manuscript (5%), analysed WES data (10%) and obtained ethics approval. PS edited the manuscript (5%), analysed histopathology reports (100%) and analysed imaging data (5%). AMM-L wrote the paper (15%), edited the manuscript (10%), conceptualised the study, obtained ethics approval and analysed WES data (20%).

  • Funding PS holds an NHMRC MRFF Next Generation Clinical Researchers Program Practitioner Fellowship (APP1137127). AMM-L held an NHMRC Early Career Fellowship (APP1158111) during this project and is currently supported by a University of Queensland Faculty of Medicine Fellowship. EM is funded by a Research Training Stipend from the Australian Department of Education. Exome sequencing was funded by an Australian Skin and Skin Cancer Research Centre ECF grant (AM and BB-S). The participants were originally recruited to the Brisbane Naevus Morphology Study (BNMS), funded by an NHMRC (APP1062935) and Centre of Research Excellence for the Study of Naevi (APP1099021). This work was also made possible by a Metro South Health Research Support Scheme Program Grant (RSS_2021_028). This research was carried out at the Frazer Institute, University of Queensland based at the Translational Research Institute (TRI), Woolloongabba, Queensland, Australia.

  • Competing interests PS is a shareholder of MoleMap Limited and e-derm consult and undertakes regular teledermatological reporting for both companies. PS is a medical consultant for Canfield Scientific and Blaze Bioscience MoleMap Australia Limited, and a medical advisor for First Derm. No other authors have conflicts to declare.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.