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Mutations in BRIP1 confer high risk of ovarian cancer.

Nature genetics (2011-10-04)
Thorunn Rafnar, Daniel F Gudbjartsson, Patrick Sulem, Aslaug Jonasdottir, Asgeir Sigurdsson, Adalbjorg Jonasdottir, Soren Besenbacher, Pär Lundin, Simon N Stacey, Julius Gudmundsson, Olafur T Magnusson, Louise le Roux, Gudbjorg Orlygsdottir, Hafdis T Helgadottir, Hrefna Johannsdottir, Arnaldur Gylfason, Laufey Tryggvadottir, Jon G Jonasson, Ana de Juan, Eugenia Ortega, Jose M Ramon-Cajal, Maria D García-Prats, Carlos Mayordomo, Angeles Panadero, Fernando Rivera, Katja K H Aben, Anne M van Altena, Leon F A G Massuger, Mervi Aavikko, Paula M Kujala, Synnöve Staff, Lauri A Aaltonen, Kristrun Olafsdottir, Johannes Bjornsson, Augustine Kong, Anna Salvarsdottir, Hafsteinn Saemundsson, Karl Olafsson, Kristrun R Benediktsdottir, Jeffrey Gulcher, Gisli Masson, Lambertus A Kiemeney, Jose I Mayordomo, Unnur Thorsteinsdottir, Kari Stefansson
PMID21964575
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.