Letter | Published:

Common variation in KITLG and at 5q31.3 predisposes to testicular germ cell cancer

Nature Genetics 41, 811–815 (2009) | Download Citation

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Abstract

Testicular germ cell tumors (TGCT) have been expected to have a strong underlying genetic component. We conducted a genome-wide scan among 277 TGCT cases and 919 controls and found that seven markers at 12p22 within KITLG (c-KIT ligand) reached genome-wide significance (P < 5.0 × 10−8 in discovery). In independent replication, TGCT risk was increased threefold per copy of the major allele at rs3782179 and rs4474514 (OR = 3.08, 95% CI = 2.29–4.13; OR = 3.07, 95% CI = 2.29–4.13, respectively). We found associations with rs4324715 and rs6897876 at 5q31.3 near SPRY4 (sprouty 4; P < 5.0 × 10−6 in discovery). In independent replication, risk of TGCT was increased nearly 40% per copy of the major allele (OR = 1.37, 95% CI = 1.14–1.64; OR = 1.39, 95% CI = 1.16–1.66, respectively). All of the genotypes were associated with both seminoma and nonseminoma TGCT subtypes. These results demonstrate that common genetic variants affect TGCT risk and implicate KITLG and SPRY4 as genes involved in TGCT susceptibility.

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Acknowledgements

We would like to thank both the men with and without TGCT and parents of individuals with TGCT who contributed to the study. We thank K. D'Andrea, B. Wubbenhorst and S. Fish for their assistance with DNA extraction and genotyping. We thank D. Pucci, K. Robertson, E. Ellis Ohr, A. Mackley, M. Shellenberger, C. Panks, K. Leach and D. Jacke for subject recruitment and database maintenance. The study was financially supported by the Abramson Cancer Center at the University of Pennsylvania, Lance Armstrong Foundation and US National Institutes of Health grants R01CA114478 (P.A.K., K.L.N.); R01CA085914 (C.C., J.R.S., S.M.S.); and Fox Chase Cancer Center Support Grant P30 CA006927 (A.K.G.). Recruitment of the UPHS controls was supported by the Cardiovascular Institute of the University of Pennsylvania. Genotyping was supported by GlaxoSmithKline through an Alternate Drug Discovery Initiative research alliance award (to M.P.R. and D.J.R.) with the University of Pennsylvania School of Medicine.

Author information

Affiliations

  1. Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Peter A Kanetsky
    • , Nandita Mitra
    • , Saran Vardhanabhuti
    •  & Mingyao Li

  2. Abramson Cancer Center, Divisions of Hematology-Oncology and Medical Genetics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Peter A Kanetsky
    • , Nandita Mitra
    • , David J Vaughn
    • , Richard Letrero
    • , Stephanie L Ciosek
    •  & Katherine L Nathanson

  3. Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • David J Vaughn

  4. Division of Medical Genetics, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Richard Letrero
    • , Stephanie L Ciosek
    • , Lauren M Smith
    •  & Katherine L Nathanson

  5. Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.

    • David R Doody
    • , Chu Chen
    • , Jacqueline R Starr
    •  & Stephen M Schwartz

  6. Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.

    • JoEllen Weaver
    •  & Andrew K Godwin

  7. Center for Applied Genomics and Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Anthony Albano
    •  & Hakon Hakonarson

  8. Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.

    • Chu Chen
    • , Jacqueline R Starr
    •  & Stephen M Schwartz

  9. Department of Pediatrics, School of Medicine, University of Washington, Seattle, Washington, USA.

    • Jacqueline R Starr

  10. Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Daniel J Rader
    •  & Muredach P Reilly

  11. Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.

    • Daniel J Rader
    •  & Muredach P Reilly

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Contributions

P.A.K., S.M.S. and K.L.N. designed the study. GWAS genotyping done by A.A. was supervised by H.H. L.M.S., R.L. and C.C. contributed to the completion of validation genotyping. P.A.K., S.V., N.M., M.L. and J.R.S. conducted the statistical analyses. S.L.C., D.J.V., J.W., D.J.R., A.K.G., M.P.R. and K.L.N. recruited individuals with and without TGCT, and S.L.C., D.R.D. and J.W. maintained database information on TGCT cases and controls. P.A.K. and K.L.N. wrote the manuscript, and all authors contributed to manuscript preparation.

Corresponding author

Correspondence to Katherine L Nathanson.

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DOI

https://doi.org/10.1038/ng.393

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