Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Common variants at 19p13 are associated with susceptibility to ovarian cancer

A Corrigendum to this article was published on 01 January 2016

This article has been updated

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women1. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10−4 and P = 6 × 10−4, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10−9 and P = 4 × 10−11, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genomic and transcript analysis of C19orf62 and ANKLE1 in the 19p13 ovarian cancer susceptibility region.

Similar content being viewed by others

Change history

  • 07 December 2015

    In the version of this article initially published, the name of author Angela Brooks-Wilson was spelled incorrectly in the author list. The error has been corrected in the HTML and PDF versions of the article.

  • 01 January 2016

    Nat. Genet. 42, 880–884 (2010); published online 19 September 2010; corrected after print 7 December 2015 In the version of this article initially published, the name of author Angela Brooks-Wilson was spelled incorrectly in the author list. The error has been corrected in the HTML and PDF versions of the article.

References

  1. Ferlay, J., Bray, F., Pisani, P. & Parkin, D.M. GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide (International Agency for Research on Cancer Press, Lyon, France, 2004).

  2. Boyd, J. Clinicopathologic features of BRCA-linked and sporadic ovarian cancer. J. Am. Med. Assoc. 283, 2260–2265 (2000).

    Article  CAS  Google Scholar 

  3. Majdak, E.J. et al. Prognostic impact of BRCA1 pathogenic and BRCA1/BRCA2 unclassified variant mutations in patients with ovarian carcinoma. Cancer 104, 1004–1012 (2005).

    Article  Google Scholar 

  4. Hindorff, L.A., Junkins, H.A., Mehta, J.P. & Manolio, T.A. A catalog of published genome-wide association studies. (accessed 13 February 2010) 〈http://www.genome.gov/gwastudies/〉.

  5. Song, H. et al. A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2. Nat. Genet. 41, 996–1000 (2009).

    Article  CAS  Google Scholar 

  6. Tomlinson, I. et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat. Genet. 39, 984–988 (2007).

    Article  CAS  Google Scholar 

  7. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447, 661–678 (2007).

  8. Goode, E. Identification of four novel ovarian cancer susceptibility loci identified in a genome-wide association study. Nat. Genet. advance online publication, doi:10.1038/ng.668 (19 September 2010).

  9. Feng, L., Huang, J. & Chen, J. MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes Dev. 23, 719–728 (2009).

    Article  CAS  Google Scholar 

  10. Shao, G. et al. MERIT40 controls BRCA1-Rap80 complex integrity and recruitment to DNA double-strand breaks. Genes Dev. 23, 740–754 (2009).

    Article  CAS  Google Scholar 

  11. Wang, B., Hurov, K., Hofmann, K. & Elledge, S.J. NBA1, a new player in the Brca1 A complex, is required for DNA damage resistance and checkpoint control. Genes Dev. 23, 729–739 (2009).

    Article  CAS  Google Scholar 

  12. Lakhani, S.R. et al. Pathology of ovarian cancers in BRCA1 and BRCA2 carriers. Clin. Cancer Res. 10, 2473–2481 (2004).

    Article  CAS  Google Scholar 

  13. Maia, A.T. et al. Extent of differential allelic expression of candidate breast cancer genes is similar in blood and breast. Breast Cancer Res. 11, R88 (2009).

    Article  Google Scholar 

  14. Yang, C., Yu, B., Zhou, D. & Chen, S. Regulation of aromatase promoter activity in human breast tissue by nuclear receptors. Oncogene 21, 2854–2863 (2002).

    Article  CAS  Google Scholar 

  15. Galindo, B.E. & Vacquier, V.D. Phylogeny of the TMEM16 protein family: some members are overexpressed in cancer. Int. J. Mol. Med. 16, 919–924 (2005).

    CAS  PubMed  Google Scholar 

  16. Antoniou, A. et al. A locus on 19p13 locus modifies risk of breast cancer for BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population. Nat. Genet. advance online publication, doi: 10.1038/ng.669 (19 September 2010).

  17. Tavassoli, F.A. & Devilee, P. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs (International Agency for Research in Cancer Press, Lyon, France, 2003).

  18. Sankararaman, S., Sridhar, S., Kimmel, G. & Halperin, E. Estimating local ancestry in admixed populations. Am. J. Hum. Genet. 82, 290–303 (2008).

    Article  CAS  Google Scholar 

  19. Scheet, P. & Stephens, M. A fast and flexible statistical model for large-scale population genotype data: applications to inferring missing genotypes and haplotypic phase. Am. J. Hum. Genet. 78, 629–644 (2006).

    Article  CAS  Google Scholar 

  20. Marchini, J., Howie, B., Myers, S., McVean, G. & Donnelly, P. A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

    Article  CAS  Google Scholar 

  21. Azzato, E.M. et al. Prevalent cases in observational studies of cancer survival: do they bias hazard ratio estimates? Br. J. Cancer 100, 1806–1811 (2009).

    Article  CAS  Google Scholar 

  22. Krzywinski, M. et al. A set of BAC clones spanning the human genome. Nucleic Acids Res. 32, 3651–3660 (2004).

    Article  CAS  Google Scholar 

  23. Dafou, D. et al. Chromosomes 6 and 18 induce neoplastic suppression in epithelial ovarian cancer cells. Int. J. Cancer 124, 1037–1044 (2009).

    Article  CAS  Google Scholar 

  24. Li, N.F. et al. A modified medium that significantly improves the growth of human normal ovarian surface epithelial (OSE) cells in vitro. Lab. Invest. 84, 923–931 (2004).

    Article  Google Scholar 

Download references

Acknowledgements

We thank all the individuals who took part in this study and 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 (United Kingdom Ovarian Cancer Population Study (UKOPS)); J. Morrison, P. Harrington and the Studies of Epidemiology and Risk Factors in Cancer Heredity (SEARCH) team (SEA); U. Eilber and T. Koehler (German Ovarian Cancer Study (GER)); D. Bowtell, A. deFazio, D. Gertig and A. Green (Australian Ovarian Cancer Study (AOCS)); A. Green, P. Parsons, N. Hayward and D. Whiteman (Australian Cancer Study (ACS)); L. Gacucova (Hannover-Minsk Ovarian Cancer Study (HMOCS)); S. Haubold, P. Schürmann, F. Kramer, W. Zheng, T.-W. Park-Simon, K. Beer-Grondke and D. Schmidt (Hannover-Jena Ovarian Cancer Study (HJOCS)); and L. Brinton, M. Sherman, A. Hutchinson, N. Szeszenia-Dabrowska, B. Peplonska, W. Zatonski, A. Soni, P. Chao and M. Stagner (NCI Ovarian Cancer Case-Control Study in Poland (POL2)).

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 makes 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 K. Sladek Smith. The results published here are in part based upon data generated by The Cancer Genome Atlas 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 at http://cancergenome.nih.gov/. S.J.R. is supported by the Mermaid/Eve Appeal. G.C.-T. and P.M.W. are supported by the National Health and Medical Research Council. P.A.F. is supported by the Deutsche Krebshilfe. M.E.G. acknowledges National Health Service funding to the National Institutes of Health Research Centre at the Royal Marsden Hospital, and D.F.E. is a Principal Research Fellow of Cancer Research UK. Funding of the constituent studies was provided by the Danish Cancer Society, the Ovarian Cancer Research Fund (PPD/RPCI.07), the Roswell Park Cancer Institute Alliance Foundation, the US National Cancer Institute (CA58860, CA92044, P50CA105009, R01CA122443, R01CA126841-01, R01CA16056, R01CA61107, R01CA71766, R01CA054419, R01CA114343, R01CA87538, R01CA112523, R01CA58598, N01CN55424, N01PC35137 and Intramural research funds), the US Army Medical Research and Material Command (DAMD17-01-1-0729), Cancer Council Victoria, Cancer Council Queensland, Cancer Council New South Wales, Cancer Council South Australia, Cancer Council Tasmania and Cancer Foundation of Western Australia, the National Health and Medical Research Council of Australia (199600 and 400281), the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401), the state of Baden-Württemberg through Medical Faculty of the University of Ulm (P.685), the Mayo Foundation, the Lon V. Smith Foundation (LVS-39420), the Oak Foundation, the University College Hospital National Institute for Health Research Biomedical Research Centre and the Royal Marsden Hospital Biomedical Research Centre.

Author information

Authors and Affiliations

Authors

Consortia

Contributions

P.D.P.P., S.A.G. and D.F.E. 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., K.L.B., G.C.-T. and E.L.G. coordinated phase 3. J.T. and K.L.B. conducted primary phase 1 and phase 2 analysis and phase 3 SNP selection. K.L.B. conducted phase 3 and combined data statistical analyses. H.S., J.B. and J.M.C. conducted phase 3 genotyping. S.A.G., M.N., C.J. and T.S. designed and performed the functional analyses. The remaining authors coordinated contributing studies. K.L.B. and P.D.P.P. drafted the manuscript with substantial input from S.A.G., H.S. and S.J.R. All authors contributed to the final draft.

Corresponding author

Correspondence to Paul D P Pharoah.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–6 and Supplementary Figures 1–4 (PDF 692 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bolton, K., Tyrer, J., Song, H. et al. Common variants at 19p13 are associated with susceptibility to ovarian cancer. Nat Genet 42, 880–884 (2010). https://doi.org/10.1038/ng.666

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.666

This article is cited by

Search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer