POT1 pathogenic variants: not all telomere pathway genes are equal in risk of hereditary cutaneous melanoma

Multiple genes important in telomere maintenance, including POT1, TERT, ACD and TERF2IP, have been associated with hereditary cutaneous malignant melanoma (CMM).¹ In this issue of the BJD, Potrony et al. describe findings of pathogenic POT1 germline variants in nearly 2% of individuals from 228 Spanish hereditary CMM families.² This work strengthens previously described connections between pathogenic variants (PVs) in genes important in telomere biology and CMM risk.

PVs in CDKN2A are the most common genetic cause of familial melanoma, occurring in 15–40% of families with a history of multiple individuals with CMM.¹ This study focuses on hereditary CMM families with at least two affected individuals who were negative for CDKN2A PVs. The results described here are consistent with previous work including a study from the U.K., the Netherlands and Australia in which POT1 pathogenic variants were identified in about 4% of CMM families.³ The frequency of POT1 PVs in CMM families reported in the literature ranges from 0% in a Dutch study to 12.5% in one Italian study.^4,5

Longer telomeres have been observed in individuals with PVs in POT1 and those with CMM and may be associated with CMM risk through influence on increased replicative potential.^4,6 POT1 is part of the shelterin complex that binds to telomeres and plays a role in protection of the chromosomal ends from loss.⁷ In particular, promoter variants in TERT that encodes the telomerase enzyme have been associated with increased risk of CMM in nonfamilial cases.⁸ Of note, in this series, Potrony et al. did not identify TERT promoter mutations in any of the familial cases but did identify one individual with multiple primary CMM carrying a rare c.−125C>T variant of uncertain clinical significance. This study, like other series, suggests that pathogenic TERT promoter variants are relatively rare in families with hereditary CMM.⁹ Conversely, POT1 PVs appear to be a more common cause of hereditary CMM.

A limitation of this study is that the pathogenicity of the POT1 variants was not confirmed. The missense variant p.Ile78Thr (c.233T>C) falls within the POT1 DNA binding domain and is predicted by in silico models to be pathogenic, but is functionally uncharacterized. Two variants identified in this study (c.255G>A and c.1792G>A) were shown to disrupt normal splicing and presumably result in a truncated protein, but these studies were only done in vitro.

This study has clinical implications for hereditary CMM and for POT1 genetic testing in melanoma prone families. Firstly, it may help to expand the phenotype associated with POT1 PVs, as one of the described families showed segregation of a POT1 PV with melanoma and thyroid cancer. Another published study also showed segregation of a POT1 variant in a family with CMM, dysplastic naevi and nonmedullary thyroid cancers.¹⁰ Secondly, POT1 is currently included on some, but not all gene panels for clinical genetic testing of hereditary melanoma. Knowledge of one’s mutation status can result in unaffected carriers receiving better screening and detection of cancers at earlier ages, which may improve outcomes. There are currently no guidelines for clinical melanoma risk management in individuals with POT1 PVs so studies like this one are critical for demonstrating the types and ages of cancer associated with these variants. Thus, these results may have utility for genetic testing laboratories who currently offer panels for hereditary melanoma and for clinicians who order genetic testing for patients with hereditary melanoma.