POT1 germline mutations but not TERT promoter mutations are implicated in melanoma susceptibility in a large cohort of Spanish melanoma families.

BACKGROUND: Germline mutations in telomere-related genes such as POT1 and the TERT promoter predispose to familial melanoma.

OBJECTIVE: To evaluate the prevalence of germline mutations in the POT1 gene and in the TERT promoter in a large cohort of Spanish melanoma-prone families (at least two affected individuals in first- or second-degree relatives).

METHODS: Overall, 228 CDKN2A wild-type melanoma-prone families were included in the study. Screening of POT1 was performed in one affected case of each family and TERT promoter was sequenced in one affected case from 202 families (26 families were excluded due to DNA exhaustion/degradation). Additionally, TERT promoter sequencing was extended to addition 30 CDKN2A mutated families and 70 sporadic multiple primary melanoma patients (MPM) with a family history of other cancers.

RESULTS: We identified four families with potentially pathogenic POT1 germline mutations: a missense variant c.233T>C (p.Ile78Thr), a nonsense variant c.1030G>T (p.Glu344*), and two variants c.255G>A (r.125_255del) and c.1792G>A (r.1791_1792insAGTA, p.Asp598Serfs*22), which we confirmed disrupted POT1 mRNA splicing. A TERT promoter variant of unknown significance (c.-125C>A) was detected in a MPM patient, but no germline mutations were detected in the TERT promoter in familial melanoma cases.

CONCLUSIONS: Overall, 1·75% of our CDKN2A/CDK4-wild type Spanish melanoma-prone families carry probably damaging mutations in POT1. The frequency of TERT promoter germline mutations in melanoma families in our population is extremely rare. This article is protected by copyright. All rights reserved.