POT1 loss-of-function variants predispose to familial melanoma

Abstract

Deleterious germline variants in CDKN2A account for around 40% of familial melanoma cases1, while rare variants in CDK4, BRCA2, BAP1, and the promoter of TERT, have also been linked to the disease2-5. Here we set out to identify novel high-penetrance susceptibility genes in unexplained cases by sequencing 184 melanoma patients from 105 pedigrees recruited in the United Kingdom, the Netherlands, and Australia that were negative for variants in known predisposition genes. We identify families where melanoma co-segregates with loss-of-function variants in the protection of telomeres 1 (POT1) gene, a proportion of members presenting with an early age of onset and multiple primaries. We show that these variants either affect POT1 mRNA splicing or alter key residues in the highly conserved oligonucleotide-/oligosaccharide-binding (OB) domains of POT1, disrupting protein-telomere binding, leading to increased telomere length. Thus, POT1 variants predispose to melanoma formation via a direct effect on telomeres.

Recent developments in brain tumor predisposing syndromes

“…Interestingly, two of the melanoma predisposing mutations (Tyr89Cys) and (Gln94Glu) were within six residues from one of the GLIOGENE mutations (Gly95Cys). One case of an undisclosed type of brain tumor occurred in the Tyr89Cys melanoma family [129], but no cases of melanoma were reported in the Gly95Cys GLIOGENE family [128]. In contrast, in colorectal cells increased levels of POT1 were seen in tumor tissues compared to adjacent normal tissues, and the relative telomere length was increased in proportion to the POT1 level [130].…”

“…POT1 has also been implicated in melanomas, and it has been claimed that as many as 4% of the tumors can be due to POT1 mutations [129]. Interestingly, two of the melanoma predisposing mutations (Tyr89Cys) and (Gln94Glu) were within six residues from one of the GLIOGENE mutations (Gly95Cys).…”

Multiple primary melanomas (MPMs) and criteria for genetic assessment: MultiMEL, a multicenter study of the Italian Melanoma Intergroup

“…However, most of the participating centers perform genetic counseling and dermatologic examinations for patients coming from other areas. Rare mutations in novel melanoma susceptibility genes, including a founder mutation in POT1 in families from the Italian region Emilia-Romagna, have been identified [31][32][33][34][35][36] but were not tested. However, such mutations occur in less than 10% of melanoma families with a yet unknown genetic prevalence in the studied populations.…”

“…[27][28][29][30] Novel melanoma susceptibility genes have also been identified, but their geographic prevalence and penetrance has yet to be established. [31][32][33][34][35][36] The aim of our study was to carry out a nationwide evaluation of the mutation rate of melanoma susceptibility genes CDKN2A, CDK4, and MITF and associated features in patients with MPM to establish whether, even in the absence of family history, MPM may be added as a criterion to update the national recommendations for genetic testing for hereditary melanoma.…”

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

“…POT1, the most significantly somatically mutated gene in the Gr and Cs B-cell lymphomas combined, encodes a protein important for telomere maintenance, and mutations in this gene predispose to several types of cancer in human (Robles-Espinoza et al 2014;Shi et al 2014). The gene is also recurrently mutated, lost, or differentially regulated in human cancers, including lymphoma (Bellon et al 2006;Vega et al 2008).…”