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

Nat Genet. 2017 Jul;49(7):1133-1140. doi: 10.1038/ng.3896. Epub 2017 Jun 12.


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.

Publication types

  • Meta-Analysis

MeSH terms

  • Adult
  • Chromatin / genetics
  • Gene Expression Profiling
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Annotation
  • Neoplasms, Germ Cell and Embryonal / epidemiology
  • Neoplasms, Germ Cell and Embryonal / genetics*
  • Polymorphism, Single Nucleotide
  • Risk
  • Testicular Neoplasms / epidemiology
  • Testicular Neoplasms / genetics*
  • Young Adult


  • Chromatin

Supplementary concepts

  • Testicular Germ Cell Tumor