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

Lookup NU author(s): Dr Jérémie Nsengimana

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).

Abstract

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.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- A nalysis 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.

Publication metadata

Author(s): Litchfield K, Levy M, Orlando G, Loveday C, Law PJ, Migliorini G, Holroyd A, Broderick P, Karlsson R, Haugen TB, Kristiansen W, Nsengimana J, Fenwick K, Assiotis I, 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

Publication type: Article

Publication status: Published

Journal: Nature Genetics

Year: 2017

Volume: 49

Issue: 7

Pages: 1133-1140

Print publication date: 01/07/2017

Online publication date: 12/06/2017

Acceptance date: 16/05/2017

Date deposited: 25/06/2020

ISSN (print): 1061-4036

ISSN (electronic): 1546-1718

Publisher: Nature Research

URL: https://doi.org/10.1038/ng.3896

DOI: 10.1038/ng.3896

PubMed id: 28604728

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