Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor

Kevin Litchfield, Max Levy, Giulia Orlando, Chey Loveday, Philip J Law, Gabriele Migliorini, Amy Holroyd, Peter Broderick, Robert Karlsson, Trine B Haugen, Wenche Kristiansen, Jérémie Nsengimana, Kerry Fenwick, Ioannis Assiotis, ZSofia Kote-Jarai, Alison M Dunning, Kenneth R Muir, Julian Peto, Rosalind Eeles, Douglas F EastonDarshna Dudakia, Nick Orr, Nora Pashayan, D Timothy Bishop, Alison Reid, Robert A Huddart, Janet Shipley, Tom Grotmol, Fredrik Wiklund, Richard S Houlston, Clare Turnbull, UK Testicular Cancer Collaboration

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Abstract

Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.

Original languageEnglish
Pages (from-to)1133-1140
Number of pages8
JournalNature Genetics
Volume49
Issue number7
DOIs
Publication statusPublished - 12 Jun 2017

Keywords

  • Journal Article

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    Litchfield, K., Levy, M., Orlando, G., Loveday, C., Law, P. J., Migliorini, G., Holroyd, A., Broderick, P., Karlsson, R., Haugen, T. B., Kristiansen, W., Nsengimana, J., Fenwick, K., Assiotis, I., Kote-Jarai, ZS., Dunning, A. M., Muir, K. R., Peto, J., Eeles, R., ... UK Testicular Cancer Collaboration (2017). Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor. Nature Genetics, 49(7), 1133-1140. https://doi.org/10.1038/ng.3896