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A genome-wide association study of testicular germ cell tumor

Nature Genetics 41, 807–810 (2009) | Download Citation

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Abstract

We conducted a genome-wide association study for testicular germ cell tumor (TGCT), genotyping 307,666 SNPs in 730 cases and 1,435 controls from the UK and replicating associations in a further 571 cases and 1,806 controls. We found strong evidence for susceptibility loci on chromosome 5 (per allele OR = 1.37 (95% CI = 1.19–1.58), P = 3 × 10−13), chromosome 6 (OR = 1.50 (95% CI = 1.28–1.75), P = 10−13) and chromosome 12 (OR = 2.55 (95% CI = 2.05–3.19), P = 10−31). KITLG, encoding the ligand for the receptor tyrosine kinase KIT, which has previously been implicated in the pathogenesis of TGCT and the biology of germ cells, may explain the association on chromosome 12.

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References

  1. 1.

    , , & GLOBOCAN 2002: Cancer Incidence, Mortality and Prevalence Worldwide, Version 2. IARC CancerBase No. 5 (IARC Press, Lyon, France, 2004).

  2. 2.

    et al. Genetic predisposition to testicular germ-cell tumours. Lancet Oncol. 5, 363–371 (2004).

  3. 3.

    , , & Testicular microlithiasis: a review and its association with testicular cancer. Urol. Oncol. 22, 285–289 (2004).

  4. 4.

    Possible carcinoma-in-situ of the testis. Lancet 2, 516–517 (1972).

  5. 5.

    et al. Germ cell tumours of the testis. Crit. Rev. Oncol. Hematol. 53, 141–164 (2005).

  6. 6.

    & et al. in Cancer: Principles and Practice of Oncology (eds. DeVita, V.T. Jr, Hellman, S. & Rosenberg, S.A.) Cancer of the Testis 1269–1290 (Lippincott Williams & Wilkins, Philadelphia, 2005).

  7. 7.

    & Familial risk in testicular cancer as a clue to a heritable and environmental aetiology. Br. J. Cancer 90, 1765–1770 (2004).

  8. 8.

    & Modification of cancer risks in offspring by sibling and parental cancers from 2,112,616 nuclear families. Int. J. Cancer 92, 144–150 (2001).

  9. 9.

    et al. Genome-wide linkage screen for testicular germ cell tumour susceptibility loci. Hum. Mol. Genet. 15, 443–451 (2006).

  10. 10.

    et al. The Y deletion gr/gr and susceptibility to testicular germ cell tumor. Am. J. Hum. Genet. 77, 1034–1043 (2005).

  11. 11.

    & What is left behind—quality control in germ cell migration. Sci. STKE 2007, pe16 (2007).

  12. 12.

    Signaling by Kit protein-tyrosine kinase–the stem cell factor receptor. Biochem. Biophys. Res. Commun. 337, 1–13 (2005).

  13. 13.

    , , & Loss of the transmembrane but not the soluble kit ligand isoform increases testicular germ cell tumor susceptibility in mice. Cancer Res. 68, 5193–5197 (2008).

  14. 14.

    , , , & Genes, chromosomes and the development of testicular germ cell tumors of adolescents and adults. Genes Chromosom. Cancer 47, 547–557 (2008).

  15. 15.

    et al. Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Cell Cycle 2, 281–282 (2003).

  16. 16.

    , , & Bcl-w forms complexes with Bax and Bak, and elevated ratios of Bax/Bcl-w and Bak/Bcl-w correspond to spermatogonial and spermatocyte apoptosis in the testis. Mol. Endocrinol. 14, 682–699 (2000).

  17. 17.

    et al. Population genomics of human gene expression. Nat. Genet. 39, 1217–1224 (2007).

  18. 18.

    et al. Familial testicular cancer: a report of the UK family register, estimation of risk and an HLA class 1 sib-pair analysis. Br. J. Cancer 65, 255–262 (1992).

  19. 19.

    & Polygenic inheritance of breast cancer: implications for design of association studies. Genet. Epidemiol. 25, 190–202 (2003).

  20. 20.

    & Genome-wide association studies in cancer. Hum. Mol. Genet. 17, R109–R115 (2008).

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Acknowledgements

We would like to thank the individuals with TGCT and the clinicians involved in their care for participation in this study. We would like to thank D. Dudakia, J. Pugh, H. McDonald and J. Marke for subject recruitment and database entry for the TGCT collections. We acknowledge NHS funding to the NIHR Biomedical Research Centre. We acknowledge use of DNA from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. D.F.E. is a Principal Research Fellow of Cancer Research UK, and the study was supported by the Institute of Cancer Research, Cancer Research UK and the Wellcome Trust.

Author information

Affiliations

  1. Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK.

    • Elizabeth A Rapley
    • , Clare Turnbull
    • , Rachel Linger
    • , Anthony Renwick
    • , Deborah Hughes
    • , Sarah Hines
    • , Sheila Seal
    • , Nazneen Rahman
    •  & Michael R Stratton

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

    • Ali Amin Al Olama
    • , Jonathan Morrison
    •  & Douglas F Easton

  3. The Wellcome Trust Sanger Institute, Hinxton, UK.

    • Emmanouil T Dermitzakis
    • , Panagiotis Deloukas
    •  & Michael R Stratton

  4. Academic Radiotherapy Unit, Institute of Cancer Research, Sutton, Surrey, UK.

    • Robert A Huddart

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

    • Jeremie Nsengimana
    •  & D Timothy Bishop

Consortia

  1. The UK Testicular Cancer Collaboration

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

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Contributions

E.A.R., D.T.B., D.F.E. and M.R.S. designed the study and obtained financial support. E.A.R., R.A.H., The UK Testicular Cancer Collaboration and M.R.S. coordinated the studies providing samples for stage 1 and stage 2. P.D. directed genotyping of stage 1. N.R. and C.T. directed genotyping of stage 2. R.L., A.R., D.H., S.H. and S.S. conducted genotyping of stage 2. E.T.D. and P.D. produced and analyzed gene expression data. A.A.A.O., J.M., J.N., D.T.B., C.T. and D.F.E. designed, coordinated and conducted statistical analyses. M.R.S. drafted the manuscript with substantial contributions from C.T., E.A.R. and D.F.E. All authors contributed to the final paper.

Corresponding author

Correspondence to Michael R Stratton.

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Tables 1–5 and Supplementary Figure 1

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DOI

https://doi.org/10.1038/ng.394

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