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 oncogenesis. 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.

中文翻译：

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确定影响睾丸生殖细胞肿瘤易感性的 19 个新风险位点和潜在调控机制。

全基因组关联研究 (GWAS) 改变了对睾丸生殖细胞肿瘤 (TGCT) 易感性的理解，但大部分遗传性仍未得到解释。在这里，我们报告了一项新的 GWAS，一项对先前 GWAS 的荟萃分析和一个复制系列，总计 7,319 个 TGCT 病例和 23,082 个对照。我们确定了 19 个新的 TGCT 风险位点，将已知 TGCT 风险位点的数量大致翻了一番，达到 44 个。通过在 TGCT 细胞中进行原位 Hi-C，我们为所有 44 个 TGCT 风险 SNP 和候选因果基因之间的物理相互作用网络提供了证据. 我们的研究结果暗示发育转录调节因子的广泛破坏是 TGCT 易感性的基础，这与作为肿瘤发生的起始步骤失败的原始生殖细胞分化一致。有缺陷的微管组装和 KIT-MAPK 信号的失调也表现为反复中断的通路。我们的研究结果支持多基因风险模型，并提供对 TGCT 生物学基础的深入了解。