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Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14

Nature Genetics volume 45, pages 686–689 (2013)Cite this article

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Abstract

Testicular germ cell tumor (TGCT) is the most common cancer in young men and is notable for its high familial risks1,2. So far, six loci associated with TGCT have been reported3,4,5,6,7. From genome-wide association study (GWAS) analysis of 307,291 SNPs in 986 TGCT cases and 4,946 controls, we selected for follow-up 694 SNPs, which we genotyped in a further 1,064 TGCT cases and 10,082 controls from the UK. We identified SNPs at nine new loci (1q22, 1q24.1, 3p24.3, 4q24, 5q31.1, 8q13.3, 16q12.1, 17q22 and 21q22.3) showing association with TGCT (P < 5 × 10−8), which together account for an additional 4–6% of the familial risk of TGCT. The loci include genes plausibly related to TGCT development. PRDM14, at 8q13.3, is essential for early germ cell specification8, and DAZL, at 3p24.3, is required for the regulation of germ cell development9. Furthermore, PITX1, at 5q31.1, regulates TERT expression and is the third TGCT-associated locus implicated in telomerase regulation10.

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Figure 1: Regional plots of the nine new loci associated with TGCT.

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Acknowledgements

We thank the subjects with TGCT and the clinicians involved in their care for participation in this study. We also thank M. Warren Perry, D. Dudakia, J. Pugh, R. Linger, J. Marke, D. Hughes and D. Pernet for recruitment of subjects and database entry for the TGCT collections, and we thank the UK Genetics of Prostate Cancer Study (UKGPCS) study teams for the recruitment of the UKGPCS controls. This study would not have been possible without the contributions of the following: P. Hall (COGS); D.F. Easton (BCAC), A. Berchuck (OCAC), R. Eeles (PRACTICAL), G. Chenevix-Trench (CIMBA), J. Dennis, A.M. Dunning, A. Lee, E. Dicks and D.F. Easton (Cambridge); J. Benitez, A. Gonzalez-Neira and the staff of the CNIO genotyping unit; J. Simard and D.C. Tessier, F. Bacot, D. Vincent, S. LaBoissière and F. Robidoux and the staff of the McGill University and Génome Québec Innovation Centre; S.E. Bojesen, S.F. Nielsen, B.G. Nordestgaard and the staff of the Copenhagen DNA laboratory; and J.M. Cunningham, S.A. Windebank, C.A. Hilker, J. Meyer and the staff of Mayo Clinic Genotyping Core Facility. We acknowledge National Health Service funding to the National Institute for Health Research Biomedical Research Centre. The COGS (Collaborative Oncological Gene-environment Study) research initiative leading to these results has received support from the European Community's Seventh Framework Programme under grant agreement 223175 (HEALTH-F2-2009-223175), Cancer Research UK (grants C1287/A10710 and C5047/A7357) and Prostate Action. This study makes use of data generated by the Wellcome Trust Case Control Consortium 2 (WTCCC2). A full list of the investigators who contributed to the generation of the data is available from the WTCCC website. D.F.E. is a Principal Research Fellow of Cancer Research UK. The initial GWAS study was supported by the Institute of Cancer Research, Cancer Research UK and the Wellcome Trust. This study was supported by the Institute of Cancer Research and Movember.

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Authors and Affiliations

  1. Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK

    Elise Ruark, Sheila Seal, Heather McDonald, Feng Zhang, Anna Elliot, KingWai Lau, Elizabeth Perdeaux, Elizabeth Rapley, Rosalind Eeles, Zsofia Kote-Jarai, Nazneen Rahman & Clare Turnbull

  2. Royal Marsden National Health Service (NHS) Foundation Trust, Fulham and Sutton, UK

    Rosalind Eeles

  3. Department of Non-communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK

    Julian Peto

  4. Warwick Medical School, University of Warwick, Coventry, UK

    Kenneth Muir

  5. Section of Epidemiology & Biostatistics, Leeds Institute of Molecular Medicine, Leeds, UK

    Jeremie Nsengimana & D Timothy Bishop

  6. Molecular Cytogenetics, The Institute of Cancer Research, Sutton, UK

    Janet Shipley

  7. The Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK

    Michael R Stratton

  8. Genetic Epidemiology Unit, Strangeways Research Laboratory, Cancer Research UK, Cambridge, UK

    Douglas F Easton

  9. Academic Radiotherapy Unit, Institute of Cancer Research, Sutton, UK

    Robert A Huddart

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  1. Elise Ruark
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Consortia

UK Testicular Cancer Collaboration (UKTCC)

Contributions

C.T. and N.R. designed the study. C.T., N.R., R.A.H. and UKTCC coordinated the studies that provided case samples. D.F.E., J.P., R.E., Z.K.-J. and K.M. coordinated studies that provided control samples. C.T., H.M., S.S. and A.E. coordinated sample management, selection and transfer. M.R.S., D.F.E., D.T.B., J.N. and E. Rapley designed and executed the original case genome-wide genotyping. C.T. designed the statistical analyses. C.T. and E. Ruark conducted statistical analyses with assistance from K.L. and F.Z. C.T. drafted the manuscript with assistance from N.R., E. Ruark, J.S., J.N., D.T.B. and E.P. All authors contributed to the final manuscript.

Corresponding author

Correspondence to Clare Turnbull.

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The authors declare no competing financial interests.

Additional information

Details appear in the Supplementary Note.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1–5, Supplementary Figure 1 (PDF 109 kb)

Supplementary Table 6

Regulatory annotation of variants within nine new TGCT loci (Excel file) (XLSX 33 kb)

Supplementary Table 7

Expression of genes within 500kb of nine new TGCT SNPs (Excel file) (XLSX 16 kb)

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Ruark, E., Seal, S., McDonald, H. et al. Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14. Nat Genet 45, 686–689 (2013). https://doi.org/10.1038/ng.2635

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