Abstract
Testicular germ cell tumors (TGCT) are the most common tumor in young white men and have a high heritability. In this study, the international Testicular Cancer Consortium assemble 10,156 and 179,683 men with and without TGCT, respectively, for a genome-wide association study. This meta-analysis identifies 22 TGCT susceptibility loci, bringing the total to 78, which account for 44% of disease heritability. Men with a polygenic risk score (PRS) in the 95th percentile have a 6.8-fold increased risk of TGCT compared to men with median scores. Among men with independent TGCT risk factors such as cryptorchidism, the PRS may guide screening decisions with the goal of reducing treatment-related complications causing long-term morbidity in survivors. These findings emphasize the interconnected nature of two known pathways that promote TGCT susceptibility: male germ cell development within its somatic niche and regulation of chromosomal division and structure, and implicate an additional biological pathway, mRNA translation.
Highlights
Our meta-analysis incorporated estimates from our published Testicular germ cell tumors (TGCT) analysis[9], genotyping data from deCODE genetics[24] and the UK Biobank[25], and summary statistics from genotypes collected from 14 studies collaborating as part of the Testicular Cancer Consortium (TECAC) (Supplementary Tables 1, 2; Supplementary Methods)
Multiple independent signals were observed at BAK1 (2), TKTL1 (2), TERT (3), DMRT1 (4), and the 19p11-p12 (6) region (Table 1; Supplementary Data 2), a complex region containing multiple KRABzinc finger proteins (Supplementary Fig. 4)
Minimal overlap is present between the 66 novel and replicated independent loci for TGCT and susceptibility loci identified in genome-wide association studies (GWAS) of other cancers (Supplementary Data 4)
Summary
Our meta-analysis incorporated estimates from our published TGCT analysis[9], genotyping data from deCODE genetics[24] and the UK Biobank[25], and summary statistics from genotypes collected from 14 studies collaborating as part of the Testicular Cancer Consortium (TECAC) (Supplementary Tables 1, 2; Supplementary Methods). Connections appearing in two or more cell lines were scored more highly than a connection found in just one cell line Based on this evaluation of the potential target genes on the autosomes, we classified 37 (37%) genes as highly likely, 25 (25%) genes as moderately likely, and 39 (39%) as unlikely to be associated with TGCT; genes with multiple classification levels were counted in the highest likelihood group (Table 1, Supplementary Data 2, 5). Genes selected for enrichment analysis included target genes (n = 62) on autosomes that scored moderately or highly likely to be associated with TGCT and all target genes (n = 7) on the X chromosome; two of these genes did not have available expression data. Of the 102 variants, 83 (81%) disrupted transcription factor binding sites
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