Testicular germ cell tumour (TGCT), the most common cancer in young men, has a significant heritable basis that has long raised questions as to the existence of underlying major high-penetrance susceptibility gene(s). To determine the contribution of rare gene mutations to the inherited risk of TGCT, we analysed germline whole-exome data for 919 TGCT cases and 1609 cancer-free controls. We compared frequencies between TGCT cases and controls of rare (<1%) and low-frequency (1-5%) coding variants (1) individually and (2) collapsed at the gene level via burden testing (T1, disruptive; T2, all deleterious; and T3, all nonsynonymous) using Fisher's exact test with Bonferroni correction of significance thresholds. No individual variant or individual gene showed a significant association with TGCT after correction for multiple testing. In the largest whole-exome sequencing study of testicular cancer reported to date, our findings do not support the existence of a major high-penetrance TGCT susceptibility gene (of odds ratio >10 and allele frequency [combined] > 0.01%). Owing to its power, this study cannot exclude the existence of susceptibility genes responsible for occasional TGCT families or of rare mutations that confer very modest relative risks. In concert with findings from genome-wide association studies, our data support the notion that inherited susceptibility is largely polygenic with substantial contribution from common variation.

Patient summary

In the largest study of its kind, we sequenced ∼20 000 genes in 919 men with testicular germ cell tumour (TGCT) and 1609 TGCT-free individuals and found no evidence of a single major gene underlying predisposition to TGCT (in the manner of BRCA1 for breast cancer). Instead, familial risk of TGCT is likely to be due to varying dosages of hundreds of minor genetic factors.

中文翻译：

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睾丸生殖细胞肿瘤（TGCT）病例的大规模测序不包括主要TGCT易感基因

睾丸生殖细胞肿瘤（TGCT）是年轻男性中最常见的癌症，具有重要的遗传基础，长期以来人们一直在质疑潜在的主要高渗透性易感基因的存在。为了确定稀有基因突变对TGCT遗传风险的贡献，我们分析了919例TGCT病例和1609例无癌对照的种系全外显子数据。我们比较了TGCT病例与罕见（<1％）和低频（1-5％）编码变体（1）的对照和（2）通过负担测试在基因水平崩溃的频率（T1，破坏性； T2，所有都是有害的； T3都是非同义的），并使用Fisher精确检验和Bonferroni校正显着性阈值。在进行多次测试校正后，没有单个变体或单个基因与TGCT有显着关联。在迄今为止报道的最大的睾丸癌全基因组测序研究中，我们的发现不支持主要的高渗透性TGCT敏感性基因（比值比> 10，等位基因频率[合]> 0.01％）。由于其强大的功能，这项研究不能排除导致TGCT家族偶然的遗传基因或具有极小的相对风险的罕见突变。与全基因组关联研究的结果相一致，我们的数据支持以下观点，即遗传易感性很大程度上是多基因的，而共同变异的贡献很大。由于其强大的功能，这项研究不能排除导致TGCT家族偶然的遗传基因或具有极小的相对风险的罕见突变。与全基因组关联研究的结果相一致，我们的数据支持以下观点，即遗传易感性很大程度上是多基因的，而共同变异的贡献很大。由于其强大的功能，这项研究不能排除导致TGCT家族偶然的遗传基因或具有极小的相对风险的罕见突变。与全基因组关联研究的结果相一致，我们的数据支持以下观点，即遗传易感性很大程度上是多基因的，而共同变异的贡献很大。

病人总结

在同类研究中，我们对919名睾丸生殖细胞肿瘤（TGCT）和1609名无TGCT的男性患者中的20000个基因进行了测序，未发现任何单一基因对TGCT易感（以BRCA1的方式）乳腺癌）。取而代之的是，TGCT的家族风险可能是由于数百种次要遗传因素的剂量不同所致。