Abstract
Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10 â+'8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
| Original language | English |
|---|---|
| Pages (from-to) | 164-171 |
| Number of pages | 8 |
| Journal | Nature Genetics |
| Volume | 47 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 2015 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2015 Nature America, Inc. All rights reserved.
Funding
including X.Q. Chen for iPLEX genotyping. The COGS project is funded through a European Commission Seventh Framework Programme grant (agreement number 223175-HEALTH-F2-2009-223175). CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium (OCAC) is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). Scientific development and funding for this project were in part supported by the US National Cancer Institute GAME-ON Post-GWAS Initiative (U19-CA148112). This study made use of data generated by the Wellcome Trust Case Control Consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based on data generated by The Cancer Genome Atlas (TCGA) Pilot Project established by the US National Cancer Institute and US National Human Genome Research Institute (database of Genotypes and Phenotypes (dbGaP) accession phs000178.v8.p7). The cBio Portal is developed and maintained by the Computational Biology Center at the Memorial Sloan-Kettering Cancer Center. S. Healey is supported by a National Health and Medical Research Council of Australia Program Grant to G.C.-T. Details of the funding of individual investigators and studies are provided in the Supplementary Note. A full list of the investigators who contributed to the generation of the data is available on the CIMBA website (see URLs).
| Funders | Funder number |
|---|---|
| National Institutes of Health | |
| US National Cancer Institute | U19-CA148112 |
| National Institutes of Health | P30CA016672, P50CA159981, U10CA180850, UL1TR000005, P30CA015083, P50CA116201, UM1CA182910, U01CA116167, U19CA148112, R01CA126841, R01CA140323, U10CA027469, UM1CA164920, ZIACP010126, R01CA176785, RC4CA153828, U10CA180838, R25CA174664, P30CA076292, U10CA180867, U10CA180822 |
| National Cancer Institute | U10CA037517 |
| Ovarian Cancer Research Fund | PPD/RPCI.07 |
| Wellcome Trust | 076113 |
| Cancer Research UK | C12292/A11174, C1287/A10118 |
| National Health and Medical Research Council | |
| Seventh Framework Programme | 223175-HEALTH-F2-2009-223175 |
