Litchfield, K, Levy, M, Orlando, G et al. (30 more authors) (2017) Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor. Nature Genetics, 49 (7). pp. 1133-1140. ISSN 1061-4036
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 oncogenesis¹. 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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 Nature America, Inc., part of Springer Nature. This is a post-peer-review, pre-copyedit version of a letter published in Nature Genetics. The final authenticated version is available online at: https://doi.org/10.1038/ng.3896 |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > Institute of Molecular Medicine (LIMM) (Leeds) > Section of Epidemiology and Biostatistics (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 25 May 2018 15:04 |
Last Modified: | 25 May 2018 19:25 |
Status: | Published |
Publisher: | Springer Nature |
Identification Number: | 10.1038/ng.3896 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:131227 |