Mutations in BRIP1 confer high risk of ovarian cancer

• Published in: Nature genetics Vol. 43; no. 11; pp. 1104 - 1107
• Main Authors: Rafnar, Thorunn, Gudbjartsson, Daniel F, Sulem, Patrick, Jonasdottir, Aslaug, Sigurdsson, Asgeir, Jonasdottir, Adalbjorg, Besenbacher, Soren, Lundin, Pär, Stacey, Simon N, Gudmundsson, Julius, Magnusson, Olafur T, le Roux, Louise, Orlygsdottir, Gudbjorg, Helgadottir, Hafdis T, Johannsdottir, Hrefna, Gylfason, Arnaldur, Tryggvadottir, Laufey, Jonasson, Jon G, de Juan, Ana, Ortega, Eugenia, Ramon-Cajal, Jose M, García-Prats, Maria D, Mayordomo, Carlos, Panadero, Angeles, Rivera, Fernando, Aben, Katja K H, van Altena, Anne M, Massuger, Leon F A G, Aavikko, Mervi, Kujala, Paula M, Staff, Synnöve, Aaltonen, Lauri A, Olafsdottir, Kristrun, Bjornsson, Johannes, Kong, Augustine, Salvarsdottir, Anna, Saemundsson, Hafsteinn, Olafsson, Karl, Benediktsdottir, Kristrun R, Gulcher, Jeffrey, Masson, Gisli, Kiemeney, Lambertus A, Mayordomo, Jose I, Thorsteinsdottir, Unnur, Stefansson, Kari
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.11.2011; Nature Publishing Group
• Subjects: 631/208/737; 631/67/581; 692/699/67/1517/1709; Agriculture; Animal Genetics and Genomics; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer prevention; Cancer Research; Developed countries; DNA-Binding Proteins - genetics; Fanconi Anemia Complementation Group Proteins; Female; Female genital diseases; Fundamental and applied biological sciences. Psychology; Gene Function; Genes; Genetic aspects; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Genomics; Gynecology. Andrology. Obstetrics; Health aspects; Health risks; Human; Human Genetics; Humans; letter; Medical schools; Medical sciences; Mutation; Ovarian cancer; Ovarian Neoplasms - genetics; Polymorphism, Single Nucleotide; Population genetics, reproduction patterns; Risk factors; RNA Helicases - genetics; Tumors; Southern Europe; Atlantic Ocean Islands; Scandinavia; Europe; Iceland; Spain; Ovarian diseases; High risk; Ovary cancer; Malignant tumor; Mutation; Single nucleotide polymorphism; Population genetics; Cancer; Female genital diseases
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.955

Using a combination of whole-genome sequencing, haplotype sharing and the genealogies of the Icelandic population, Thorunn Rafnar, Kari Stefansson and colleagues identified a rare coding mutation in the gene of a BRCA1-interacting factor, BRIP1 , that confers a high relative risk of ovarian cancer. 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.