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 × 10−8. Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.
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Acknowledgements
We thank all the individuals who took part in this study and all the researchers, clinicians, and technical and administrative staff who made possible the many studies contributing to this work (a full list is provided in the Supplementary Note), 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).
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Writing group: K.B.K., A.C.A., G.C.-T., S.J.R., J. Beesley, P.P.P., S.G. Performed statistical analyses for CIMBA: K.B.K. Performed statistical analyses for OCAC: J.T. Performed the meta-analyses: K.B.K. CIMBA database management: L.M. and D.B. Supervised CIMBA statistical analyses, meta-analyses and CIMBA data management: A.C.A. Supervised OCAC statistical analyses: P.P.P. Initiated and coordinated CIMBA: G.C.-T. Coordinated OCAC: A. Berchuck and P.P.P. Conceived and coordinated the synthesis of the iCOGS array: D.F.E. Coordinated iCOGS genotyping: J.S., K. Offit, F.J.C. iCOGS genotyping, calling and quality control: J.M. Cunningham, J.D., P.S., D.F.E., K.B.K., J.T., P.P.P., A.C.A., G.C.-T. Programming support: A. Lee. Provided DNA samples and/or phenotypic data: S.J.R., J.T., A. Lee, H.C.S., K.L., S. Healey, J.M.L., T.J.S., Y.G.L., T.P., Y.B., Q.L., S.C., D.H., A. Miron, M. Southey, M.B.T., D.E.G., S.S.B., R.J., C.M.D., E.J.v.R., S.L.N., Y.C.D., T.V.O.H., L.J., A.-M.G., B.E., J.D., J. Benitez, A.O., M.J.G., I. Komenaka, J.N.W., P.G., P.P., L. Bernard, A.V., B.B., B.P., S. Manoukian, P.R., L.P., L.O., F.F., I. Konstantopoulou, J. Garber, D.F., J. Perkins, R.P., S.E., EMBRACE, A.K.G., R.K.S., A. Meindl, C.E., C.S., O.M.S., GEMO, F.D., S. Mazoyer, D.S.-L., K. Claes, K.D.L., J. Kirk, G.C.R., M. Piedmonte, D.M.O., M.d.l.H., T.C., K.A., H. Nevanlinna, J.M. Collée, M.A. Rookus, J.C.O., F.B.L.H., HEBON, E.O., O.D., I.B., J. Brunet, C.L., M.A.P., A. Jakubowska, J. Gronwald, J. Lubinski, G.S., R.B.B., M. Plante, J.S., P.S., M.M., S. Tognazzo, M.R.T., KConFab, V.S.P., X. Wang, N.L., C.I.S., N.K., J.V., C.A.A., G.P., A. Berger, C.F.S., M.-K.T., C.M.P., M.H.G., P.L.M., G.R., A.M.M., S. Tchatchou, I.L.A., G.G., A.E.T., U.B.J., T.A.K., M. Thomassen, A. Bojesen, J.Z., E.F., Y.L., M. Soller, A. Liljegren, B.A., Z.E., M.S.-A., O.I.O., R.L.N., T.R.R., K.L.N., S.M.D., K.H.L., B.Y.K., C.W., J. Lester, Australian Cancer Society, Australian Ovarian Cancer Study Group, A.H., A.B.E., M.W.B., P.A.F., D. Lambrechts, E.V.N., I.V., S. Lambrechts, E.D., J.A.D., K.G.W., M.A. Rossing, A.R., J.C.-C., S.W.-G., U.E., K.B.M., K. Odunsi, L.S., S. Lele, L.R.W., M.T.G., P.J.T., Y.B.S., I.B.R., M.D., P. Hillemanns, T.D., N.A., N.B., A. Leminen, L.M.P., R.B., F.M., J.L.K., R.P.E., R.B.N., A.d.B., F.H., I.S., P. Harter, K.M., S. Hosono, S.O., A. Jensen, S.K.K., E.H., H.N.H., M.A.N.A., S.-H.T., Y.-L.W., B.L.F., E.L.G., J.M. Cunningham, R.A.V., F.B., G.G.G., D. Liang, M.A.T.H., X. Wu, D.A.L., M.B., A. Berchuck, E.S.I., J.M.S., P.C., R.P.W., D.W.C., K.L.T., E.M.P., S.S.T., E.V.B., I.O., S.H.O., C.K., H.B.S., I.L.T., L. Bjorge, A.M.v.A., K.K.H.A., L.A.K., L.F.A.G.M., M.K., A.B.-W., L.E.K., L.S.C., N.D.L., C.C., H.Y., J. Lissowska, L.A.B., N.W., C.H., L.L., L.N., H.B., H.S., D.E., I.G.C., I.M., J. Paul, K. Carty, N.S., R.G., A.S.W., J.H.R., V.M., W.S., B.-T.J., W.Z., X.-O.S., Y.-T.G., B.R., H.A.R., J.R.M., S.A.N., A.N.M., A.C., H.-Y.L., J.P.-W., T.A.S., Y.-Y.T., Z.C., A.Z., H.A.-C., A.G.-M., U.M., P. Harrington, A.W.L., A.H.W., C.L.P., G.C., M.C.P., A.D.-M., A.T., I.K.R., J. Kupryjanczyk, M.F., H. Noushmehr, L.T., N.T., U.H., C.I., M. Tischkowitz, E.N.I., M.A.C., D.F.E., K. Offit, F.J.C., S.G., P.P.P., A.C.A., G.C.-T. All authors read and approved the final manuscript.
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A full list of members appears in the Supplementary Note.
A full list of members appears in the Supplementary Note.
A full list of members appears in the Supplementary Note.
A full list of members appears in the Supplementary Note.
A full list of members appears in the Supplementary Note.
A full list of members appears in the Supplementary Note.
A full list of members appears in the Supplementary Note.
A full list of members appears in the Supplementary Note.
Integrated supplementary information
Supplementary Figure 1 Imputation accuracy distribution.
Histogram showing the distribution of imputation accuracy estimates r2 in the first genotype imputation on the 1000 Genomes Project data v3 for SNPs with MAF > 0.05 (a,c,e) and for SNPs with MAF ≤ 0.05 (b,d,f) in OCAC-iCOGS (a,b), BRCA1 mutation carriers (c,d) and BRCA2 mutation carriers (e,f).
Supplementary Figure 2 Imputation accuracy distribution.
Histogram showing the distribution of imputation accuracy estimates r2 in the first genotype imputation on the 1000 Genomes Project data v3 for SNPs with MAF > 0.05 (a,c,e) and for SNPs with MAF ≤ 0.05 (b,d,f) in the UK GWAS (a,b), the US GWAS (c,d) and the Mayo GWAS (e,f).
Supplementary Figure 3 Quantile-quantile plot for genetic variants from the genotype imputation.
The column on the left shows all variants, and the right column shows variants not located in regions previously known to be associated with invasive ovarian cancer.
Supplementary Figure 4 Meta-analysis risk associations.
Manhattan plots showing the meta-analysis associations of genetic variants with risk of any subtype of ovarian cancer (a,b) and serous subtype ovarian cancer (c,d) for all genetic variants available after the first imputation (a,c) and after excluding SNPs located within known ovarian cancer susceptibility loci (b,d).
Supplementary Figure 5 Regional association plots for each novel locus based on the meta-analysis.
For 17q11.2, the meta-analysis was based on OCAC and BRCA2 mutation carriers only. For 1p34.3 and 6p22.1, the OCAC analysis was based on serous ovarian cancer. SNPs genotyped by the iCOGS array are shown in magenta, and imputed SNPs are shown in black.
Supplementary Figure 6 Ovarian cancer susceptibility loci at chromosome 1 and chromosome 4.
The Manhattan plot depicts the strength of association between all imputed and genotyped SNPs across the regions at chromosome 1 (a) and chromosome 4 (b). The dotted line represents the genome-wide significance level 5 × 10−8. FAIRE-seq data revealing potential regulatory regions in ovarian and fallopian tube cells are depicted as black bars. Additional tracks show genes and enhancers in ovary as described in Hnisz et al.38. Positions of SNPs for which imputation r2 < 0.3 and/or minor allele frequency < 0.005 are shown in the bottom track as ‘untyped’ SNPs.
Supplementary Figure 7 Ovarian cancer susceptibility loci at chromosome 6 and chromosome 9.
The Manhattan plot depicts the strength of association between all imputed and genotyped SNPs across the regions at chromosome 6 (a) and chromosome 9 (b). The dotted line represents the genome-wide significance level 5 × 10−8. FAIRE-seq data revealing potential regulatory regions in ovarian and fallopian tube cells are depicted as black bars. Additional tracks show genes and enhancers in ovary as described in Hnisz et al.38. Positions of SNPs for which imputation r2 < 0.3 and/or minor allele frequency < 0.005 are shown in the bottom track as ‘untyped’ SNPs.
Supplementary Figure 8 Ovarian cancer susceptibility locus at chromosome 17.
The Manhattan plot depicts the strength of association between all imputed and genotyped SNPs across the regions at chromosome 17. The dotted line represents the genome-wide significance level 5 × 10−8. FAIRE-seq data revealing potential regulatory regions in ovarian and fallopian tube cells are depicted as black bars. Additional tracks show genes and enhancers in ovary as described in Hnisz et al.38. Positions of SNPs for which imputation r2 < 0.3 and/or minor allele frequency < 0.005 are shown in the bottom track as ‘untyped’ SNPs.
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Kuchenbaecker, K., Ramus, S., Tyrer, J. et al. Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nat Genet 47, 164–171 (2015). https://doi.org/10.1038/ng.3185
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DOI: https://doi.org/10.1038/ng.3185
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