title: Mutations in BRIP1 confer high risk of ovarian cancer.
abstract: Ovarian cancer causes more deaths than any other gynecologic malignancy in developed countries. Sixteen million sequence variants, identified through whole-genome sequencing of 457 Icelanders, were imputed to 41,675 Icelanders genotyped using SNP chips, as well as to their relatives. Sequence variants were tested for association with ovarian cancer (N of affected individuals = 656). We discovered a rare (0.41% allelic frequency) frameshift mutation, c.2040_2041insTT, in the BRIP1 (FANCJ) gene that confers an increase in ovarian cancer risk (odds ratio (OR) = 8.13, P = 2.8 × 10(-14)). The mutation was also associated with increased risk of cancer in general and reduced lifespan by 3.6 years. In a Spanish population, another frameshift mutation in BRIP1, c.1702_1703del, was seen in 2 out of 144 subjects with ovarian cancer and 1 out of 1,780 control subjects (P = 0.016). This allele was also associated with breast cancer (seen in 6/927 cases; P = 0.0079). Ovarian tumors from heterozygous carriers of the Icelandic mutation show loss of the wild-type allele, indicating that BRIP1 behaves like a classical tumor suppressor gene in ovarian cancer.
authors.affiliation: deCODE genetics, Reykjavik, Iceland. thorunn.rafnar@decode.is
authors.forename: Thorunn
authors.initials: T
authors.lastname: Rafnar
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gudbjartsson
authors.forename: Patrick
authors.initials: P
authors.lastname: Sulem
authors.forename: Aslaug
authors.initials: A
authors.lastname: Jonasdottir
authors.forename: Asgeir
authors.initials: A
authors.lastname: Sigurdsson
authors.forename: Adalbjorg
authors.initials: A
authors.lastname: Jonasdottir
authors.forename: Soren
authors.initials: S
authors.lastname: Besenbacher
authors.forename: Pär
authors.initials: P
authors.lastname: Lundin
authors.forename: Simon N
authors.initials: SN
authors.lastname: Stacey
authors.forename: Julius
authors.initials: J
authors.lastname: Gudmundsson
authors.forename: Olafur T
authors.initials: OT
authors.lastname: Magnusson
authors.forename: Louise
authors.initials: L
authors.lastname: le Roux
authors.forename: Gudbjorg
authors.initials: G
authors.lastname: Orlygsdottir
authors.forename: Hafdis T
authors.initials: HT
authors.lastname: Helgadottir
authors.forename: Hrefna
authors.initials: H
authors.lastname: Johannsdottir
authors.forename: Arnaldur
authors.initials: A
authors.lastname: Gylfason
authors.forename: Laufey
authors.initials: L
authors.lastname: Tryggvadottir
authors.forename: Jon G
authors.initials: JG
authors.lastname: Jonasson
authors.forename: Ana
authors.initials: A
authors.lastname: de Juan
authors.forename: Eugenia
authors.initials: E
authors.lastname: Ortega
authors.forename: Jose M
authors.initials: JM
authors.lastname: Ramon-Cajal
authors.forename: Maria D
authors.initials: MD
authors.lastname: García-Prats
authors.forename: Carlos
authors.initials: C
authors.lastname: Mayordomo
authors.forename: Angeles
authors.initials: A
authors.lastname: Panadero
authors.forename: Fernando
authors.initials: F
authors.lastname: Rivera
authors.forename: Katja K H
authors.initials: KK
authors.lastname: Aben
authors.forename: Anne M
authors.initials: AM
authors.lastname: van Altena
authors.forename: Leon F A G
authors.initials: LF
authors.lastname: Massuger
authors.forename: Mervi
authors.initials: M
authors.lastname: Aavikko
authors.forename: Paula M
authors.initials: PM
authors.lastname: Kujala
authors.forename: Synnöve
authors.initials: S
authors.lastname: Staff
authors.forename: Lauri A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: Kristrun
authors.initials: K
authors.lastname: Olafsdottir
authors.forename: Johannes
authors.initials: J
authors.lastname: Bjornsson
authors.forename: Augustine
authors.initials: A
authors.lastname: Kong
authors.forename: Anna
authors.initials: A
authors.lastname: Salvarsdottir
authors.forename: Hafsteinn
authors.initials: H
authors.lastname: Saemundsson
authors.forename: Karl
authors.initials: K
authors.lastname: Olafsson
authors.forename: Kristrun R
authors.initials: KR
authors.lastname: Benediktsdottir
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Gulcher
authors.forename: Gisli
authors.initials: G
authors.lastname: Masson
authors.forename: Lambertus A
authors.initials: LA
authors.lastname: Kiemeney
authors.forename: Jose I
authors.initials: JI
authors.lastname: Mayordomo
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
mesh_terms: D004268:DNA-Binding Proteins / Q000235:genetics*; D051856:Fanconi Anemia Complementation Group Proteins; D005260:Female; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020365:RNA Helicases / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D051856:Fanconi Anemia Complementation Group Proteins; C000618935:BRIP1 protein, human; D020365:RNA Helicases