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

Author(s)

Publication date

2017-06-12

Series/Report no

Nature Genetics;Volume 49, Issue 7

Publisher

Nature Publishing Group

Document type

Abstract

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.

Keywords

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acceptedVersion

Permanent URL (for citation purposes)

  • https://hdl.handle.net/10642/6047