POT1 clinical risk management is an open question

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.

An interesting observation is the relatively older age at cancer onset in POT1 variant carriers, with the exception of the prostate cancer cases. This, at first glance, is surprising, because we typically associate heritable cancer syndromes with earlier age at cancer onset. However, cancers associated with at least some telomere disorders may be an exception. As we age, our telomeres shorten. Telomere shortening may in turn precipitate a crisis in individuals with inherited defects in telomere maintenance mechanisms. POT1 is a member of the shelterin complex, a 6-protein structure involved in the capping of telomeres. It is assumed that the oncogenic effects of pathogenic variants in POT1 are mediated by defects in telomere maintenance. Individuals with POT1 variants typically have longer peripheral blood leukocyte telomeres than average. Interestingly, individuals with long telomeres may have an increased risk of cancer [4]. If so, then deleterious variants in other members of the Shelterin complex may contribute to the overall frequency of this syndrome. To date, germline variants in TINF2, TERF1, TERF2 and TERF2IP have been associated with cancer risk and long telomeres. Again, more data are needed on the role of these genes, from both population and familial studies. The maturation of large-scale clinically annotated whole genome population studies, such as the Gnomad and Genome England datasets, will help address some of these questions.

While many important details remain to be addressed, clinical risk management guidelines are already being proposed [5]. Baptista Freitas et al. endorse a clinical risk management approach that recognizes the importance of skin surveillance for melanoma, whole-body MRI for sarcomas, and consideration of prostate-specific antigen (PSA) testing for early-onset prostate cancer. The uncertainties around tumor spectrum, penetrance and pathogenicity, suggest that prospective studies (including surveillance), analogous to those undertaken for other multi-organ cancer syndromes, e.g., Li–Fraumeni syndrome, will be required to address many questions. We need to know what advice to give to relatives regarding cancer risk; whether to include methods of optimal melanoma surveillance, blood tests (PSA, full blood count, iron levels, multi-cancer early detection tests), imaging modalities (dedicated brain, whole body, thyroid ultrasound), fecal occult blood testing; and the sensitivity and specificity of these techniques; and the optimal intervals required for detection of cancers at a curable stage. Only with combined efforts moving forward will clinical risk management of POT1 be adequately informed.

Author contributions

The authors contributed equally to drafting and finalizing the commentary.

Competing interests

The authors declare no competing interests.