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POT 1 germline mutations but not TERT promoter mutations are implicated in melanoma susceptibility in a large cohort of Spanish melanoma families
Author(s) -
Potrony M.,
PuigButille J.A.,
RiberaSola M.,
Iyer V.,
RoblesEspinoza C.D.,
Aguilera P.,
Carrera C.,
Malvehy J.,
Badenas C.,
Landi M.T.,
Adams D.J.,
Puig S.
Publication year - 2019
Publication title -
british journal of dermatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.304
H-Index - 179
eISSN - 1365-2133
pISSN - 0007-0963
DOI - 10.1111/bjd.17443
Subject(s) - cdkn2a , germline mutation , germline , genetics , missense mutation , biology , melanoma , mutation , nonsense mutation , cancer research , gene
Summary Background Germline mutations in telomere‐related genes such as POT 1 and TERT predispose individuals to familial melanoma. Objectives To evaluate the prevalence of germline mutations in POT 1 and TERT in a large cohort of Spanish melanoma‐prone families (at least two affected first‐ or second‐degree relatives). Methods Overall, 228 CDKN 2A wild‐type melanoma‐prone families were included in the study. Screening of POT 1 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 CDKN 2A 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 POT 1 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_1792ins AGTA , p.Asp598Serfs*22), which we confirmed disrupted POT 1 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 CDKN 2A/ CDK 4 ‐wild type Spanish melanoma‐prone families carry probably damaging mutations in POT 1 . The frequency of TERT promoter germline mutations in families with melanoma in our population is extremely rare.