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Meta-analysis identifies four new loci associated with testicular germ cell tumor

Nature Genetics volume 45, pages 680–685 (2013)Cite this article

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Abstract

We conducted a meta-analysis to identify new susceptibility loci for testicular germ cell tumor (TGCT). In the discovery phase, we analyzed 931 affected individuals and 1,975 controls from 3 genome-wide association studies (GWAS). We conducted replication in 6 independent sample sets comprising 3,211 affected individuals and 7,591 controls. In the combined analysis, risk of TGCT was significantly associated with markers at four previously unreported loci: 4q22.2 in HPGDS (per-allele odds ratio (OR) = 1.19, 95% confidence interval (CI) = 1.12–1.26; P = 1.11 × 10−8), 7p22.3 in MAD1L1 (OR = 1.21, 95% CI = 1.14–1.29; P = 5.59 × 10−9), 16q22.3 in RFWD3 (OR = 1.26, 95% CI = 1.18–1.34; P = 5.15 × 10−12) and 17q22 (rs9905704: OR = 1.27, 95% CI = 1.18–1.33; P = 4.32 × 10−13 and rs7221274: OR = 1.20, 95% CI = 1.12–1.28; P = 4.04 × 10−9), a locus that includes TEX14, RAD51C and PPM1E. These new TGCT susceptibility loci contain biologically plausible genes encoding proteins important for male germ cell development, chromosomal segregation and the DNA damage response.

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Figure 1: Regional association plots, recombination plots and LD structure for the four new TGCT susceptibility regions at 4q22.2, 7p22.3, 16q22.3 and 17q22.

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Acknowledgements

The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations indicate endorsement by the US Government. We thank C. Berg and P. Prorok, Division of Cancer Prevention, NCI, the screening center investigators and the staff of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, T. Riley and staff at Information Management Services, Inc., and B. O'Brien and staff at Westat, Inc., for their contributions to the PLCO Cancer Screening Trial. We thank S. Ciosek, M. McDermoth and K. D'Andrea for expert assistance in conducting TestPAC. We thank L. Kolonel and L. Le Marchand for providing access to the Multiethnic Cohort aggressive prostate cancer scan, as well as J.P. Lewinger, M. Pike, D.J. Van Den Berg and K. Siegmund for technical and scientific contributions to the parent study at USC.

A portion of this work was supported by the Intramural Research Program of the NCI and by support services contract HHSN261200655004C with Westat, Inc. The Penn GWAS (UPENN) and replication effort for the TestPAC study were supported by the Abramson Cancer Center at the University of Pennsylvania and US National Institutes of Health grant R01CA114478 to P.A.K. and K.L.N. The replication effort for the ATLAS study was supported by US National Institutes of Health grant R01CA085914 to S.M.S. The analysis of the USC GWAS controls was supported by the Multiethnic Cohort Study (NCI U01-CA98758). The analyses of the USC GWAS testicular cases and the Familial Study were supported by the California Cancer Research Program (99-00505V-10260 and 03-00174VRS-30021) and by an NCI grant (R01CA102042) to V.K.C. and a Whittier Foundation award to the Norris Comprehensive Cancer Center. The study at MD Anderson was supported by the Center for Translational and Public Health Genomics of the Duncan Family Institute for Cancer Prevention and Risk Assessment and by an MD Anderson Senior Research Trust Fellowship to X.W. The UK testicular cancer study was supported by the Institute of Cancer Research, Cancer Research UK and the Wellcome Trust and made use of control data generated by the Wellcome Trust Case Control Consortium 2 (WTCCC2). Support was provided by the Norwegian Cancer Society to R.A.L. and R.I.S., by Health Region South-Eastern Norway to R.A.L. and S.D.F., and by the Norwegian ExtraFoundation for Health and Rehabilitation to S.D.F.

Author information

Author notes

  1. Christian P Kratz

    Present address: Present address: Center for Pediatrics and Adolescent Medicine, Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.,

  2. Charles C Chung, Peter A Kanetsky, Zhaoming Wang, Michelle A T Hildebrandt, Roelof Koster, Rolf I Skotheim, Christian P Kratz, Clare Turnbull and Victoria K Cortessis: These authors contributed equally to this work.

  3. Stephen J Chanock and Katherine L Nathanson: These authors jointly directed this work.

Authors and Affiliations

  1. Division of Cancer Epidemiology and Genetics, US Department of Health and Human Services, National Cancer Institute (NCI), US National Institutes of Health, Bethesda, Maryland, USA

    Charles C Chung, Zhaoming Wang, Christian P Kratz, Michael B Cook, Kevin B Jacobs, Larissa A Korde, Jennifer T Loud, Meredith Yeager, Mark H Greene, Katherine A McGlynn & Stephen J Chanock

  2. Division of Cancer Epidemiology and Genetics, Cancer Genome Research Laboratory, SAIC-Frederick, NCI-Frederick, Frederick, Maryland, USA

    Charles C Chung, Zhaoming Wang, Kevin B Jacobs & Meredith Yeager

  3. Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Peter A Kanetsky & Katherine L Nathanson

  4. Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Peter A Kanetsky

  5. Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

    Michelle A T Hildebrandt & Xifeng Wu

  6. Department of Medicine, Translational Medicine and Human Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Roelof Koster & Katherine L Nathanson

  7. Department of Cancer Prevention, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway

    Rolf I Skotheim, Anne C Bakken, Sigrid M Kraggerud & Ragnhild A Lothe

  8. Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway

    Rolf I Skotheim, Anne C Bakken, Sigrid M Kraggerud & Ragnhild A Lothe

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

    Clare Turnbull & Nazneen Rahman

  10. Department of Preventive Medicine, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA

    Victoria K Cortessis, Duncan C Thomas & Fredrick R Schumacher

  11. Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Cancer Research UK Clinical Centre at Leeds, St. James's University Hospital, Leeds, UK

    D Timothy Bishop

  12. Walter Reed Army Institute of Research, Silver Spring, Maryland, USA

    R Loren Erickson

  13. Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, University of Oslo, Oslo, Norway

    Sophie D Fosså

  14. Division of Medical Oncology, University of Washington/Seattle Cancer Care Alliance, Seattle, Washington, USA

    Larissa A Korde

  15. Department of Urology, Stanford University, Stanford, California, USA

    Eila C Skinner

  16. Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA

    Stephen M Schwartz

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

    Stephen M Schwartz

Authors
  1. Charles C Chung
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  2. Peter A Kanetsky
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  30. Katherine L Nathanson
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Contributions

S.J.C. and K.L.N. supervised the overall study. P.A.K., M.A.T.H., C.P.K., V.K.C., A.C.B., D.T.B., M.B.C., R.L.E., S.D.F., L.A.K., S.M.K., N.R., E.C.S., X.W., M.H.G., S.M.S., K.A.M. and K.L.N. contributed to recruitment, study and data management. C.C.C., P.A.K., Z.W., M.A.T.H., R.K., R.I.S., C.T., K.B.J., R.A.L., J.T.L., D.C.T., M.Y. and F.R.S. contributed to genotyping or association analysis of individual studies. C.C.C., Z.W. and R.K. carried out the meta-analysis and the additional reported ENCODE analyses. C.C.C. and K.L.N. prepared the manuscript, together with P.A.K., R.K. and S.J.C., and all authors reviewed and contributed to the manuscript.

Corresponding author

Correspondence to Katherine L Nathanson.

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The authors declare no competing financial interests.

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Chung, C., Kanetsky, P., Wang, Z. et al. Meta-analysis identifies four new loci associated with testicular germ cell tumor. Nat Genet 45, 680–685 (2013). https://doi.org/10.1038/ng.2634

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