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POT1 clinical risk management is an open question

European Journal of Human Genetics volume 33, pages 3–4 (2025)Cite this article

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The Original Article was published on 05 June 2024

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Over the past decade, heritable deleterious variants in POT1 have been associated with an increased risk for cancer. As always, a genetic association with disease risk will remain of scientific interest rather than clinical management until we understand better the population frequency, cancer spectrum, penetrance and pathogenicity of variants associated with POT1, as well of course as establishing effective mechanisms for modifying that risk. Baptista Freitas et al. report on three cancer-prone families carrying distinct POT1 variants [1].

Studies of affected families play an important role in both defining the cancer spectrum associated with POT1 and estimating penetrance by segregation. It seems clear that melanoma and sarcomas form part of the core cancer spectrum associated with germline variants in POT1 [2, 3]. Other cancer types traditionally associated with POT1 variants include chronic lymphatic leukemia, and glioma. More recently, thyroid cancer, colorectal cancer and lymphoid malignancies have also been associated. In addition to these cancers, Baptista Freitas et al. report an increased incidence of early-onset prostate cancer in the three POT1 families described. We note that in the three cases of early-onset prostate cancer, only one case was a known POT1 carrier, while two of the three families reported by the authors carry POT1 variants which would now be regarded as variants of uncertain significance. With under 100 families identified and many of these individuals identified in specific cancer cohorts, e.g., melanoma, there is much inherent ascertainment bias. Expanded studies of families such as those described by Baptista Freitas et al. will be critical to quantitatively define the cancer spectrum and penetrance of variants in POT1, and will help to define the pathogenicity of individual variants in these genes.

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References

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Authors and Affiliations

  1. Genomic Cancer Medicine Laboratory, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

    Mandy L. Ballinger & David M. Thomas

  2. Centre for Molecular Oncology, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia

    Mandy L. Ballinger & David M. Thomas

  3. Omico, Kensington, NSW, Australia

    Mandy L. Ballinger & David M. Thomas

Authors
  1. Mandy L. Ballinger
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  2. David M. Thomas
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The authors contributed equally to drafting and finalizing the commentary.

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Correspondence to Mandy L. Ballinger.

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The authors declare no competing interests.

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Ballinger, M.L., Thomas, D.M. POT1 clinical risk management is an open question. Eur J Hum Genet 33, 3–4 (2025). https://doi.org/10.1038/s41431-024-01676-x

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