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.
This retrospective study aimed to identify prognostic factors in patients with brain metastases from cutaneous melanoma.,In all, 265 patients under regular screening according to valid national surveillance guidelines were included in the study.,Kaplan-Meier analyses were performed to estimate and to compare overall survival.,Cox modeling was used to identify independent determinants of the overall survival, which were used in explorative classification and regression tree analysis to define meaningful prognostic groups.,In total, 55.5% of our patients presented with two or less brain metastases, 82.6% had concurrent extracranial metastasis and 64% were asymptomatic and diagnosed during surveillance scans.,In all, 36.7% were candidates for local treatment (neurosurgery or stereotactic radiosurgery (SRS)).,The median overall survival of the entire collective was 5.0 months (95% confidence interval: 4.3-5.7).,Favourable independent prognostic factors were: normal pre-treatment level of serum lactate dehydrogenase (P<0.001), administered therapy (neurosurgery or SRS vs other, P=0.002), number of brain metastases (single vs multiple, P=0.032) and presence of bone metastasis (false vs true, P=0.044).,Three prognostic groups with significantly different overall survival were identified.,Candidates for local treatment (group I) had the longer median survival (9 months).,Remaining patients could be further classified in two groups on the basis of serum lactate dehydrogenase.,Applied treatment and serum lactate dehydrogenase levels were independent predictors of survival of patients with brain metastases from cutaneous melanoma.,Patients receiving local therapy have overall survival comparable with general stage IV melanoma patients.