A genome-wide association study identifies susceptibility loci for ovarian cancer at 2q31 and 8q24

Abstract

Ovarian cancer accounts for more deaths than all other gynecological cancers combined. To identify common low-penetrance ovarian cancer susceptibility genes, we conducted a genome-wide association study of 507,094 SNPs in 1,768 individuals with ovarian cancer (cases) and 2,354 controls, with follow up of 21,955 SNPs in 4,162 cases and 4,810 controls, leading to the identification of a confirmed susceptibility locus at 9p22 (in BNC2)1. Here, we report on nine additional candidate loci (defined as having P ≤ 10−4) identified after stratifying cases by histology, which we genotyped in an additional 4,353 cases and 6,021 controls. We confirmed two new susceptibility loci with P ≤ 5 × 10−8 (8q24, P = 8.0 × 10−15 and 2q31, P = 3.8 × 10−14) and identified two additional loci that approached genome-wide significance (3q25, P = 7.1 × 10−8 and 17q21, P = 1.4 × 10−7). The associations of these loci with serous ovarian cancer were generally stronger than with other cancer subtypes. Analysis of HOXD1, MYC, TIPARP and SKAP1 at these loci and of BNC2 at 9p22 supports a functional role for these genes in ovarian cancer development.

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Figure 1: Genomic architecture of the four new ovarian cancer susceptibility regions identified from the EOC-GWAS.
Figure 2: Gene expression analysis for five candidate EOC susceptibility genes.

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Acknowledgements

We thank all the individuals who took part in this study. We thank all the researchers, clinicians and administrative staff who have made possible the many studies contributing to this work. In particular, we thank A. Ryan and J. Ford (UKO); J. Morrison, P. Harrington and the SEARCH team (SEA); U. Eilber and T. Koehler (GER); D. Bowtell, A. deFazio, D. Gertig, A. Green, P. Parsons, N. Hayward and D. Whiteman (AUS); L. Gacucova (HMO); S. Haubold, P. Schürmann, F. Kramer, W. Zheng, T.-W. Park-Simon, K. Beer-Grondke and D. Schmidt (HJO); and L. Brinton, M. Sherman, A. Hutchinson, N. Szeszenia- Dabrowska, B. Peplonska, W. Zatonski, A. Soni, P. Chao and M. Stagner (POL1). The genotyping and data analysis for this study was supported by a project grant from Cancer Research UK. We acknowledge the computational resources provided by the University of Cambridge (CamGrid). This study made use of data generated by the Wellcome Trust Case Control consortium. A full list of the investigators who contributed to the generation of the data is available from http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith.

The MAL study is supported by grants from Mermaid 1, the Danish Cancer Society and the National Cancer Institute, Bethesda, Maryland, USA (R01-CA-61107). The MAY study and the phase 3 and combined analyses were supported by the US National Institutes of Health, National Cancer Institute grants R01-CA-122443 and funding from the Mayo Foundation. The PBCS was funded by Intramural Research Funds of the US National Cancer Institute, Department of Health and Human Services. The Fox Chase Cancer Center ovarian cancer study, part of the National Cancer Institute collaboration, is supported by an Ovarian Cancer Specialized Program of Research Excellence (SPORE) (P50 CA083638). The NCO study is supported by the US National Institutes of Health, National Cancer Institute grant R01-CA-76016. The SEA study is funded by a programme grant from Cancer Research UK. We thank the SEARCH team and the Eastern Cancer Registration and Information Centre for subject recruitment. The TBO study was supported by the US National Institutes of Health (R01-CA106414); the American Cancer Society (CRTG-00-196-01-CCE); and the Advanced Cancer Detection Center Grant, Department of Defense (DAMD17-98-1-8659). The TOR study was supported by grants from the Canadian Institutes for Health Research, the National Cancer Institute of Canada with funds provided by the Canadian Cancer Society and the US National Institutes of Health (R01-CA-63682 and R01-CA-63678). Additional support for the TOR, NCO, MAY, TBO and NCI studies was provided by the University of California, Irvine grant R01-CA-114343. The UCI study is supported by the US National Institutes of Health, National Cancer Institute grants CA-58860, CA-92044 and the Lon V Smith Foundation grant LVS-39420. The UKO study is supported by funding from Cancer Research UK, the Eve Appeal and the OAK Foundation. Some of this work was undertaken at University College London Hospital/University College London, who received a proportion of funding from the Department of Health's National Institutes for Health Research Biomedical Research Centre funding scheme. We particularly thank I. Jacobs, E. Wozniak, A. Ryan, J. Ford and N. Balogun for their contribution to the study. The AUS study is supported by the National Health and Medical Research Council of Australia (199600), US Army Medical Research and Materiel Command under DAMD17-01-1-0729 (award no. W81XWH-06-1-0220) and the Cancer Council Tasmania and Cancer Foundation of Western Australia. G.C.-M.T. and P.M.W. are Research Fellows of the National Health and Medical Research Council. The Australian Ovarian Cancer Study (AOCS) Management Group (D. Bowtell, A. deFazio, G.C.-T., D.G., A.K.G. and P.M.W.) gratefully acknowledges the contribution of all the clinical and scientific collaborators (see http://www.aocstudy.org/). The Australian Cancer Study (ACS) Management Group comprises P.D.P.P., P.M.W., A. Green, N. Hayward and D. Whiteman. The BAV study is supported by the ELAN Foundation and Erlangen University Hospital. The BEL study is supported by the National Cancer Plan-Action 29 for the support of Translational Research. The DOV study (Seattle Diseases of the Ovary) was supported by the US National Institutes of Health grants R01-CA-112523 and R01-CA-87538. The GER study was supported by the German Federal Ministry of Education and Research of Germany, the Programme of Clinical Biomedical Research (01 GB 9401), and the genotyping was supported in part by the state of Baden-Württemberg through the Medical Faculty, University of Ulm (P.685). Data management was supported by the German Cancer Research Center. The HAW study was supported by the US Public Health Service grant R01-CA-58598 and contracts N01-CN-55424, N01-PC-67001 and N01-PC-35137 from the National Cancer Institute, US National Institutes of Health, Department of Health and Human Services. Funding for the USC study was received from the California Cancer Research Program grants 00-01389V-20170 and 2110200, US Public Health Service grants CA14089, CA17054, CA61132, CA63464, N01-PC-67010 and R03-CA113148 and the California Department of Health Services sub-contract 050-E8709 as part of its statewide cancer reporting program (University of Southern California). The HJO study gratefully acknowledges the contribution of F. Kramer and W. Zheng to the recruitment of subjects at Hannover Medical School. The HMO study gratefully acknowledges the help of L. Gacucova in sample preparation. The HOC study was financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland and the Finnish Cancer Society.

Author information

P.D.P.P., S.A.G., D.F.E. and A.B. designed the overall study and obtained financial support. P.D.P.P., S.A.G., S.J.R. and H.S. coordinated the studies used in phase 1 and phase 2. H.S., G.C.-T. and E.L.G. coordinated phase 3. J.T. and H.S. conducted primary phase 1 and phase 2 analyses and phase 3 SNP selection. H.S., J.B. and J.M.C. conducted phase 3 genotyping, R.A.V. and M.C.L. conducted phase 3 and combined data statistical analyses, and S.A.G., M.N. and K. Lawrenson designed and performed 'functional' analysis of candidate genes. E.L.G. and S.A.G. drafted the manuscript with substantial input from G.C.-T., H.S., S.J.R., T.A.S. and P.D.P.P. The remaining authors coordinated contributing studies, and all authors contributed to the final draft.

Correspondence to Simon A Gayther.

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A full list of members is provided in the Supplementary Note.

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Supplementary Note, Supplementary Tables 1–11 and Supplementary Figures 1–3 (PDF 1157 kb)

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