Identification of seven new ovarian cancer susceptibility loci; risk of ovarian cancer in the general population and in BRCA1 and BRCA2 carriers. K. Kuchenbaecker1, J. Tyrer1, F. J. Couch2, S. A. Gayther3, P. P. Pharoah1, S. J. Ramus3, A. C. Antoniou1, G. Chenevix-Trench4, CIMBA and OCAC 1) Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; 2) Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, Rochester, MN, USA; 3) Department of Preventive Medicine, Keck School of Medicine, University of Southern California, California, USA; 4) Department of Genetics and Computational Biology, Queensland Institute of Medical Research, Brisbane, Australia.
Twelve ovarian cancer susceptibility loci have been identified through genome wide association studies (GWAS), including a single nucleotide polymorphisms (SNP) at 4q32.3 which only appears to be associated with risk in BRCA1 mutation carriers, but not in the general population or in BRCA2 mutation carriers. Using data from two consortia participating in the Collaborative Oncological Gene-environment Study (COGS) we have carried out meta-analyses for ovarian cancer risk in the general population (n=15,437 invasive, including 9,627 serous, ovarian cancer cases and 30,845 controls) and in BRCA1 (n=2,462 affected and 12,790 unaffected) and BRCA2 (n=631 affected and 7,580 unaffected) mutation carriers using genotypes from the iCOGS chip and imputed data on 11.4M SNPs based on 1000 Genomes data as the reference panel. We assessed associations with ovarian cancer risk in mutation carriers with a retrospective likelihood approach, and in the unselected population by logistic regression. We identified (P< 5x10-8) three new loci for risk of invasive ovarian cancer in carriers and the general population (rs3820282 in WNT4 at 1p36.23, 9:136149709 in ABO at 9q34.2, rs8044477 in GOT2 at 16q21), three new loci for risk of ovarian cancer in carriers and serous invasive cancer in the general population (rs12039431 in RSPO1 at 1p34.3, rs17329882 in SYNPO2 at 4q26, rs115344852 in GPX5 at 6p22.1), and one new locus (17:29181220 in ATAD5 at 17q11.2) for risk of ovarian cancer in the general population and BRCA2 mutation carriers (OR=1.11, 95%CI: 1.08-1.14) for which there was no evidence of association in BRCA1 mutation carriers (OR=0.98, 95%CI: 0.91-1.05). Although the target of these associations will not be known until fine mapping and functional analyses have been done, it is interesting that WNT4 is a GWAS hit for endometriosis, and RSPO1 regulates Wnt4 expression in the ovary. The ABO blood group has previously been reported to be associated with risk of ovarian cancer, so is likely to be the target of the association with 9:136149709. These results demonstrate the, mostly, shared genetic basis of ovarian cancer susceptibility in the general population and in BRCA1/2 carriers and illustrate the benefits of combining data from different cancer consortia. The identification of multiple loci modifying ovarian cancer risk may be potentially useful for counselling women with BRCA1 and BRCA2 mutations about their risk of ovarian cancer.
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