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.
This is a preview of subscription content
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ferlay, J. et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127, 2893–2917 (2010).
Stratton, J.F., Pharoah, P., Smith, S.K., Easton, D. & Ponder, B.A. A systematic review and meta-analysis of family history and risk of ovarian cancer. Br. J. Obstet. Gynaecol. 105, 493–499 (1998).
Rafnar, T. et al. BRCA2, but not BRCA1, mutations account for familial ovarian cancer in Iceland: a population-based study. Eur. J. Cancer 40, 2788–2793 (2004).
Ramus, S.J. & Gayther, S.A. The contribution of BRCA1 and BRCA2 to ovarian cancer. Mol. Oncol. 3, 138–150 (2009).
Malander, S. et al. The contribution of the hereditary nonpolyposis colorectal cancer syndrome to the development of ovarian cancer. Gynecol. Oncol. 101, 238–243 (2006).
Rubin, S.C. et al. BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing. Am. J. Obstet. Gynecol. 178, 670–677 (1998).
Song, H. et al. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat. Genet. 41, 996–1000 (2009).
Goode, E.L. et al. A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24. Nat. Genet. 42, 874–879 (2010).
Bolton, K.L. et al. Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat. Genet. 42, 880–884 (2010).
Kong, A. et al. Detection of sharing by descent, long-range phasing and haplotype imputation. Nat. Genet. 40, 1068–1075 (2008).
Holm, H. et al. A rare variant in MYH6 is associated with high risk of sick sinus syndrome. Nat. Genet. 43, 316–320 (2011).
Sulem, P. et al. Identification of low-frequency variants associated with gout and serum uric acid levels. Nat. Genet. (in the press).
Thorlacius, S. et al. A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat. Genet. 13, 117–119 (1996).
Cantor, S.B. et al. BACH1, a novel helicase-like protein, interacts directly with BRCA1 and contributes to its DNA repair function. Cell 105, 149–160 (2001).
Litman, R. et al. BACH1 is critical for homologous recombination and appears to be the Fanconi anemia gene product FANCJ. Cancer Cell 8, 255–265 (2005).
Levitus, M. et al. The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J. Nat. Genet. 37, 934–935 (2005).
Levran, O. et al. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat. Genet. 37, 931–933 (2005).
Seal, S. et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat. Genet. 38, 1239–1241 (2006).
Sarantaus, L. et al. Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland. Eur. J. Hum. Genet. 8, 757–763 (2000).
Cantor, S.B. & Guillemette, S. Hereditary breast cancer and the BRCA1-associated FANCJ/BACH1/BRIP1. Future Oncol. 7, 253–261 (2011).
Yu, X., Chini, C.C., He, M., Mer, G. & Chen, J. The BRCT domain is a phospho-protein binding domain. Science 302, 639–642 (2003).
Kumaraswamy, E. & Shiekhattar, R. Activation of BRCA1/BRCA2-associated helicase BACH1 is required for timely progression through S phase. Mol. Cell. Biol. 27, 6733–6741 (2007).
Bridge, W.L., Vandenberg, C.J., Franklin, R.J. & Hiom, K. The BRIP1 helicase functions independently of BRCA1 in the Fanconi anemia pathway for DNA crosslink repair. Nat. Genet. 37, 953–957 (2005).
Godwin, A.K. et al. A common region of deletion on chromosome 17q in both sporadic and familial epithelial ovarian tumors distal to BRCA1. Am. J. Hum. Genet. 55, 666–677 (1994).
Tavtigian, S.V. et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat. Genet. 12, 333–337 (1996).
Wetzels, J.F., Kiemeney, L.A., Swinkels, D.W., Willems, H.L. & den Heijer, M. Age- and gender-specific reference values of estimated GFR in Caucasians: the Nijmegen Biomedical Study. Kidney Int. 72, 632–637 (2007).
Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25, 1754–1760 (2009).
Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).
Kong, A. et al. A high-resolution recombination map of the human genome. Nat. Genet. 31, 241–247 (2002).
This work was partly funded by the European Commission 7th Framework Programme FP7-MC-IAPP (grant agreement no. 218071 CancerGene).
Some of the authors employed by deCODE genetics own stock or stock options in the company.
About this article
Cite this article
Rafnar, T., Gudbjartsson, D., Sulem, P. et al. Mutations in BRIP1 confer high risk of ovarian cancer. Nat Genet 43, 1104–1107 (2011). https://doi.org/10.1038/ng.955
Scientific Reports (2022)
Ovarian toxicity of carboplatin and paclitaxel in mouse carriers of mutation in BRIP1 tumor suppressor gene
Scientific Reports (2022)
Cooperative interaction between ERα and the EMT-inducer ZEB1 reprograms breast cancer cells for bone metastasis
Nature Communications (2022)
Sequencing for germline mutations in Swedish breast cancer families reveals novel breast cancer risk genes
Scientific Reports (2021)
Genome Instability & Disease (2021)