| Literature DB >> 28604728 |
Kevin Litchfield1, Max Levy1, Giulia Orlando1, Chey Loveday1, Philip J Law1, Gabriele Migliorini1, Amy Holroyd1, Peter Broderick1, Robert Karlsson2, Trine B Haugen3, Wenche Kristiansen3, Jérémie Nsengimana4, Kerry Fenwick5, Ioannis Assiotis5, ZSofia Kote-Jarai1, Alison M Dunning6, Kenneth Muir7,8, Julian Peto9, Rosalind Eeles1,10, Douglas F Easton6,11, Darshna Dudakia1, Nick Orr12, Nora Pashayan13, D Timothy Bishop4, Alison Reid14, Robert A Huddart15, Janet Shipley16, Tom Grotmol17, Fredrik Wiklund2, Richard S Houlston1, Clare Turnbull1,18,19.
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.Entities:
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Year: 2017 PMID： 28604728 PMCID： PMC6016736 DOI： 10.1038/ng.3896
Source DB: PubMed Journal: Nat Genet ISSN： 1061-4036 Impact factor: 38.330