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

Litchfield, K; Levy, M; Orlando, G; Loveday, C; Law, PJ; Migliorini, G; Holroyd, A; ... Turnbull, C; + view all (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. 10.1038/ng.3896. Green open access

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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 newTGCT 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.

Type: Article
Title: Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor
Open access status: An open access version is available from UCL Discovery
DOI: 10.1038/ng.3896
Publisher version: http://doi.org/10.1038/ng.3896
Language: English
Additional information: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, GENOME-WIDE ASSOCIATION, GALLOWAY-MOWAT SYNDROME, CAPTURE HI-C, CANCER-RISK, GENOTYPE IMPUTATION, COLORECTAL-CANCER, BREAST-CANCER, VARIANTS, CHROMATIN, PROTEIN
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Epidemiology and Health > Applied Health Research
URI: https://discovery.ucl.ac.uk/id/eprint/1559332
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