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The role of germline alterations in the DNA damage response genes BRIP1 and BRCA2 in melanoma susceptibility
Author(s) -
Tuominen Rainer,
Engström Pär G.,
Helgadottir Hildur,
Eriksson Hanna,
Unneberg Per,
Kjellqvist Sanela,
Yang Muyi,
Lindén Diana,
Edsgärd Daniel,
Hansson Johan,
Höiom Veronica
Publication year - 2016
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22363
Subject(s) - melanoma , genetics , germline , biology , germline mutation , gene , allele , genetic predisposition , cancer , cancer research , phenotype , mutation
We applied a targeted sequencing approach to identify germline mutations conferring a moderately to highly increased risk of cutaneous and uveal melanoma. Ninety‐two high‐risk melanoma patients were screened for inherited variation in 120 melanoma candidate genes. Observed gene variants were filtered based on frequency in reference populations, cosegregation with melanoma in families and predicted functional effect. Several novel or rare genetic variants in genes involved in DNA damage response, cell‐cycle regulation and transcriptional control were identified in melanoma patients. Among identified genetic alterations was an extremely rare variant (minor allele frequency of 0.00008) in the BRIP1 gene that was found to cosegregate with the melanoma phenotype. We also found a rare nonsense variant in the BRCA2 gene (rs11571833), previously associated with cancer susceptibility but not with melanoma, which showed weak association with melanoma susceptibility in the Swedish population. Our results add to the growing knowledge about genetic factors associated with melanoma susceptibility and also emphasize the role of DNA damage response as an important factor in melanoma etiology. © 2016 Wiley Periodicals, Inc.