Genome-wide significant risk associations for mucinous ovarian carcinoma

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Abstract

Genome-wide association studies have identified several risk associations for ovarian carcinomas but not for mucinous ovarian carcinomas (MOCs). Our analysis of 1,644 MOC cases and 21,693 controls with imputation identified 3 new risk associations: rs752590 at 2q13 (P = 3.3 × 10−8), rs711830 at 2q31.1 (P = 7.5 × 10−12) and rs688187 at 19q13.2 (P = 6.8 × 10−13). We identified significant expression quantitative trait locus (eQTL) associations for HOXD9 at 2q31.1 in ovarian (P = 4.95 × 10−4, false discovery rate (FDR) = 0.003) and colorectal (P = 0.01, FDR = 0.09) tumors and for PAX8 at 2q13 in colorectal tumors (P = 0.03, FDR = 0.09). Chromosome conformation capture analysis identified interactions between the HOXD9 promoter and risk-associated SNPs at 2q31.1. Overexpressing HOXD9 in MOC cells augmented the neoplastic phenotype. These findings provide the first evidence for MOC susceptibility variants and insights into the underlying biology of the disease.

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Figure 1: Manhattan plots showing association.
Figure 2: The epigenetic landscape of MOC risk-associated regions.
Figure 3: eQTLs in MOC risk-associated regions.
Figure 4: 3C analysis of the 2q31.1 region containing HOXD9 performed in the EFO-27 MOC cell line.
Figure 5: Modeling the effects of HOXD9 overexpression in two in vitro models of MOC.

Change history

  • 15 July 2015

    In the version of this article initially published online, three authors’ names were given incorrectly: Xiaoqing Chen as Xiaoqin Chen, Noor Azmi Mat Adenan as Mat Adenan Noor Azmi, and Wlodzimierz Sawicki as Sawicki Wlodzmierz. The errors have been corrected for the print, PDF and HTML versions of this article.

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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). The COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement 223175–HEALTH-F2-2009-223175). 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). The scientific development and funding for this project were supported in part by Genetic Associations and Mechanisms in Oncology (GAME-ON) and a National Cancer Institute Cancer Post-GWAS Initiative (U19-CA148112). Details of the funding of individual investigators and studies are provided in the Supplementary Note. 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. A full list of the investigators who contributed to the generation of the data is available from the consortium website (see URLs). The results published here are based in part on data generated by The Cancer Genome Atlas (TCGA) Pilot Project established by the National Cancer Institute and National Human Genome Research Institute; information about TCGA and the investigators and institutions who constitute the TCGA research network can be found on the project website (see URLs).

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L.E.K., K. Lawrenson, P.D.P.P., S.A.G. and A.B. wrote the manuscript. C.M.P. and G.C.-T. coordinated and prepared samples for genotyping. L.E.K., K. Lawrenson, J.T. and P.D.P.P. carried out data analysis including imputation, genotype quality control, association analysis, in silico analyses and in vitro analyses. Q.L. and M.L.F. performed the eQTL analysis. The remaining authors contributed samples or technical expertise. All authors read and approved the final version of the manuscript.

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Correspondence to Simon A Gayther.

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A full list of members appears in the Supplementary Note.

A full list of members appears in the Supplementary Note.

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The Ovarian Cancer Association Consortium., Kelemen, L., Lawrenson, K. et al. Genome-wide significant risk associations for mucinous ovarian carcinoma. Nat Genet 47, 888–897 (2015). https://doi.org/10.1038/ng.3336

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