title: The role of germline alterations in the DNA damage response genes BRIP1 and BRCA2 in melanoma susceptibility.
abstract: 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.
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rainer
authors.initials: R
authors.lastname: Tuominen
authors.affiliation: Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Pär G
authors.initials: PG
authors.lastname: Engström
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.|Department of Oncology, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Hildur
authors.initials: H
authors.lastname: Helgadottir
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.|Department of Oncology, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Eriksson
authors.affiliation: Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Unneberg
authors.affiliation: Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors.forename: Sanela
authors.initials: S
authors.lastname: Kjellqvist
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Muyi
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Oncology, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Diana
authors.initials: D
authors.lastname: Lindén
authors.affiliation: Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, KTH Royal Institute of Technology, Solna, Sweden.
authors.forename: Daniel
authors.initials: D
authors.lastname: Edsgärd
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.|Department of Oncology, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Hansson
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Veronica
authors.initials: V
authors.lastname: Höiom
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D024682:BRCA2 Protein / Q000235:genetics*; D016022:Case-Control Studies; D004249:DNA Damage / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D010375:Pedigree; D011379:Prognosis; D020365:RNA Helicases / Q000235:genetics*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; C000618935:BRIP1 protein, human; D020365:RNA Helicases