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

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 oncogenesis1. 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.

Whole exome sequencing identifies PLEC, EXO5 and DNAH7 as novel susceptibility genes in testicular cancer

“…Genetic basis of TGCT in the Spanish population, suggesting the need of a combination of several variants. Our results are in agreement with other GWAS [10][11][12][13][14][15][16][17][18][19][20][21][22] and with the last large-scale sequencing study recently performed in TGCT cases, 33 which indicate that although familial TGCT has a strong genetic component, 6 the genetic basis in this tumour is determined by coinheritance of multiple risk variants. [2][3][4][5][6] In order to confirm that the five identified variants could confer susceptibility risk to the TGCT development, we replicated our results in a second series from the TGCA and ExAC databases (Supporting Information Fig.…”

“…Recent Genome Wide Association studies (GWAS) transformed our understanding of TGCT susceptibility. A group of 52 independent loci has been already identified to be associated with TGCT susceptibility, suggesting that a polygenic model fits better with the genetic landscape of the disease . Since no Spanish genetic studies have been performed to date, the aim of this work was to explore the genetic background of the Spanish population.…”

“…A group of 52 independent loci has been already identified to be associated with TGCT susceptibility, suggesting that a polygenic model fits better with the genetic landscape of the disease. [10][11][12][13][14][15][16][17][18][19][20][21][22] Since no Spanish genetic studies have been performed to date, the aim of this work was to explore the genetic background of the Spanish population. We performed Whole exome sequencing (WES) on Spanish familial TGCT cases and then, a case control association study with the selected variants in order to identify new variants that could contribute to the development of the disease and may have important implications in the final diagnosis and consequently useful for genetic counseling.…”

Current knowledge of risk factors for testicular germ cell tumors

“…In contrast, genome‐wide association studies have had remarkable success in identifying genetic risks associated with TGCT and have identified more than 40 risk loci (Fig. ) . These studies have shown that common allele variations in KITLG , known as stem cell factor, which encodes Kitl, is the strongest genetic risk factor for TGCT .…”

“…Not surprisingly, many other risk loci were found in sex determination‐related gene regions, such as DMRT1 (9q24), GATA4 (8p23), DAZL (3p24) and PRDM14 (8q13) . DMRT1 encodes a transcriptional factor.…”