Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor
A partir d'une méta-analyse d'études d'association sur le génome entier et menée à partir des données portant sur 7 319 patients atteints d'une tumeur germinale du testicule et sur 23 082 témoins, cette étude d'association sur le génome entier indentifie 19 nouveaux loci de susceptibilité à la maladie et met en évidence les interactions entre 44 polymorphismes à simple nucélotide de gènes impliqués dans l'étiologie de la maladie
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 oncogenesis1. 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.