Two new loci and gene sets related to sex determination and cancer progression are associated with susceptibility to testicular germ cell tumor

Hum Mol Genet. 2015 Jul 15;24(14):4138-46. doi: 10.1093/hmg/ddv129. Epub 2015 Apr 15.


Genome-wide association (GWA) studies have reported 19 distinct susceptibility loci for testicular germ cell tumor (TGCT). A GWA study for TGCT was performed by genotyping 610 240 single-nucleotide polymorphisms (SNPs) in 1326 cases and 6687 controls from Sweden and Norway. No novel genome-wide significant associations were observed in this discovery stage. We put forward 27 SNPs from 15 novel regions and 12 SNPs previously reported, for replication in 710 case-parent triads and 289 cases and 290 controls. Predefined biological pathways and processes, in addition to a custom-built sex-determination gene set, were subject to enrichment analyses using Meta-Analysis Gene Set Enrichment of Variant Associations (M) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (I). In the combined meta-analysis, we observed genome-wide significant association for rs7501939 on chromosome 17q12 (OR = 0.78, 95% CI = 0.72-0.84, P = 1.1 × 10(-9)) and rs2195987 on chromosome 19p12 (OR = 0.76, 95% CI: 0.69-0.84, P = 3.2 × 10(-8)). The marker rs7501939 on chromosome 17q12 is located in an intron of the HNF1B gene, encoding a member of the homeodomain-containing superfamily of transcription factors. The sex-determination gene set (false discovery rate, FDRM < 0.001, FDRI < 0.001) and pathways related to NF-κB, glycerophospholipid and ether lipid metabolism, as well as cancer and apoptosis, was associated with TGCT (FDR < 0.1). In addition to revealing two new TGCT susceptibility loci, our results continue to support the notion that genes governing normal germ cell development in utero are implicated in the development of TGCT.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Cell Line, Tumor
  • Chromosomes, Human, Pair 17 / genetics
  • Chromosomes, Human, Pair 19 / genetics
  • Disease Progression
  • Genetic Loci*
  • Genetic Markers
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genotyping Techniques
  • Humans
  • Logistic Models
  • Male
  • NF-kappa B / genetics
  • NF-kappa B / metabolism
  • Neoplasms, Germ Cell and Embryonal / genetics*
  • Norway
  • Polymorphism, Single Nucleotide
  • Sweden
  • Testicular Neoplasms / genetics*


  • Genetic Markers
  • NF-kappa B

Supplementary concepts

  • Testicular Germ Cell Tumor