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Mutations in BRIP1 confer high 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.

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Figure 1: A schematic view of the locus on 17q23 that is associated with ovarian cancer.

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NCBI Reference Sequence


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This work was partly funded by the European Commission 7th Framework Programme FP7-MC-IAPP (grant agreement no. 218071 CancerGene).

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Authors and Affiliations



The study was designed and supervised by T.R., D.F.G., P.S., U.T. and K.S. Statistical analysis was carried out by D.F.G, P.S., S.B. and A.K. Patient ascertainment, recruitment, biological material collection and collection of clinical and lifestyle information was organized and carried out by L.T., J.G.J., A.d.J., E.O., J.M.R.-C., M.D.G.-P., C.M., A.P., F.R., K.K.H.A., A.M.v.A., L.F.A.G.M., M.A., P.M.K., S.S., L.A.A., K. Olafsdottir, J.B., A. Salvarsdottir, H.S., K. Olafsson, K.R.B., J. Gulcher, L.A.K. and J.I.M. Principal investigators for the follow up populations were J.I.M. (Spain), L.A.K. (Netherlands) and L.A.A. and S.S. (Finland). Genotyping and laboratory experiments were designed and carried out by Aslaug Jonasdottir, Adalbjorg Jonasdottir, A. Sigurdsson, S.N.S., J. Gudmundsson, O.T.M., L.l.R., G.O., H.T.H. and H.J. Bioinformatics analysis was carried out by A.G., P.L. and G.M. Authors T.R., D.F.G., P.S., U.T. and K.S. wrote the manuscript. All authors contributed to the final version of the paper.

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Correspondence to Thorunn Rafnar or Kari Stefansson.

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Some of the authors employed by deCODE genetics own stock or stock options in the company.

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Supplementary Note, Supplementary Tables 1–9 and Supplementary Figures 1–3 (PDF 1632 kb)

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Rafnar, T., Gudbjartsson, D., Sulem, P. et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet 43, 1104–1107 (2011).

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