Identification of 19 novel loci reveals gene regulatory mechanisms determining susceptibility to testicular germ cell tumour
Testicular germ cell tumour (TGCT) is the most common cancer in young men1,2, and is characterised by strong inherited genetic risk factors3. Here we have undertaken large-scale genome wide association study (GWAS) for TGCT, encompassing ~7,500 cases and ~23,000 controls, through the Oncoarray consortium. We identified 19 novel loci, approximately doubling the number of known TGCT risk loci to 44 (P<5x10-8)4-14 and conduct deep, high-throughput functional annotation of all risk loci. We establish a network of physical interactions for all risk SNPs to candidate casual genes in 3D space, using high-throughput chromosome conformation capture techniques (HiC) in TGCT cells. Firstly, functional evidence reveals widespread disruption of developmental transcriptional regulators, consistent with failed primordial germ cell differentiation as an initiating step in TGCT oncogenesis15. We secondly observe multiple risk loci associated with defective microtubule assembly, compatible with the high level of aneuploidy observed in TGCTs, suggesting gross chromosomal instability. Finally KIT-MAPK signalling features as a recurrently dysregulated pathway. In summary our findings substantially increase the number of known TGCT risk alleles, and provides a functional basis for disease susceptibility.
- Type: Other
- Archiver: EGA European Genome-Phenome Archive
Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data
|EGAD00010001246||Infinium OncoArray-500K BeadChip||7422|
|EGAD00010001247||Infinium OncoArray-500K BeadChip||3206|
Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor.
Nat Genet 49: 2017 1133-1140
Validation of loci at 2q14.2 and 15q21.3 as risk factors for testicular cancer.
Oncotarget 9: 2018 12630-12638