Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor
Journal article, Peer reviewed
Accepted version
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https://hdl.handle.net/10642/6047Utgivelsesdato
2017-06-12Metadata
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Originalversjon
Litchfield K, Levy, Orlando, Loveday, Law, Migliorini G, Holroyd, Broderick P, Karlsson R, Haugen TB, Kristiansen W, Nsengimana, Fenwick, Assiotis, Kote-Jarai Z, Dunning AM, Muir K, Peto J, Eeles R, Easton DF, Dudakia D, Orr N, Pashayan N, Bishop DT, Reid A, Huddart RA, Shipley J, Grotmol T, Wiklund F, Houlston RS, Turnbull C. Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor. Nature Genetics. 2017;49(7):1133-1140 http://dx.doi.org/10.1038/ng.3896Sammendrag
Genome-wide association studies (GWAS) have transformed our understanding of testicular germ cell tumour (TGCT) susceptibility but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, approximately 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 between all 44 TGCT risk SNPs and candidate causal genes. Our findings reveal 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 signalling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.