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

M Potrony, JA Puig‐Butille… - British Journal of …, 2019 - academic.oup.com
M Potrony, JA Puig‐Butille, M Ribera‐Sola, V Iyer, CD Robles‐Espinoza, P Aguilera…
British Journal of Dermatology, 2019academic.oup.com
Background Germline mutations in telomere‐related genes such as POT1 and TERT
predispose individuals to familial melanoma. Objectives To evaluate the prevalence of
germline mutations in POT1 and TERT in a large cohort of Spanish melanoma‐prone
families (at least two affected 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 person from each family and TERT was sequenced in …
Background
Germline mutations in telomere‐related genes such as POT1 and TERT predispose individuals to familial melanoma.
Objectives
To evaluate the prevalence of germline mutations in POT1 and TERT in a large cohort of Spanish melanoma‐prone families (at least two affected 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 person from each family and TERT was sequenced in one affected patient from 202 families (26 families were excluded owing to DNA exhaustion/degradation). TERT promoter sequencing was extended to an additional 30 families with CDKN2A mutation and 70 patients with sporadic multiple primary melanoma (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 other 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 patient with MPM, but no germline mutations were detected in TERT promoter in cases of familial melanoma.
Conclusions
Overall, 1·7% of our CDKN2A/CDK4‐wild type Spanish melanoma‐prone families carry probably damaging mutations in POT1. The frequency of TERT promoter germline mutations in families with melanoma in our population is extremely rare.
Oxford University Press