Loss-of-Function POT1 Variants Increase Familial Melanoma Risk

Cutaneous malignant melanoma accounts for most skin cancer–related deaths, with approximately 10% of cases occurring in a familial setting. Germline variants in CDKN2A underlie 20% to 40% of familial cutaneous malignant melanoma cases and rare variants in CDK4, BAP1, and the TERT promoter have been observed at low frequency, but additional predisposition genes remain to be identified. Shi and colleagues identified germline protection of telomeres 1 (POT1) variants in patients with CDKN2A–wild-type cutaneous malignant melanoma across melanoma-prone families from Italy, the United States, and France. POT1 variants were detected at a frequency comparable with that observed for CDKN2A variants in familial cutaneous malignant melanoma cases but not control genomes. POT1 is a member of the shelterin complex, which binds telomeric DNA and maintains telomere length and integrity. The identified POT1 variants were found to occur at conserved residues within the oligonucleotide/oligosaccharide–binding (OB) domain and predicted to be functionally deleterious. Consistent with this prediction, telomere length and fragility were increased in the cells of individuals with POT1 variants compared with age-matched melanoma cases without variants. In another study, Robles-Espinoza and colleagues also identified POT1 missense variants in approximately 4% of CDKN2A–and CDK4–wild-type cutaneous malignant melanoma patient genomes from families based in the United Kingdom, the Netherlands, and Australia. These authors also found that telomere length was increased in carriers of POT1 missense variants, and observed that POT1 OB domain variants were unable to bind telomeric DNA repeats in vitro. Interestingly, POT1 variant carriers and immediate relatives were also shown to develop a variety of other cancers, and somatic POT1 missense variants were found to preferentially occur near functional residues in pan-cancer sequencing databases, suggesting that POT1 variants may predispose individuals to a broad range of cancers. Together, these studies highlight POT1 as a high-penetrance susceptibility gene in familial cutaneous malignant melanoma and implicate deregulated telomere homeostasis in melanoma predisposition.

Shi J, Yang XR, Ballew B, Rotunno M, Calista D, Fargnoli MC, et al. Rare missense variants in POT1 predispose to familial cutaneous malignant melanoma. Nat Genet 2014 Mar 30 [Epub ahead of print].

Robles-Espinoza CD, Harland M, Ramsay AJ, Aoude LG, Quesada V, Ding Z, et al. POT1 loss-of-function variants predispose to familial melanoma. Nat Genet 2014 Mar 30 [Epub ahead of print].