Kuzbari Zeid, Rowlands Charlie F, Wade Isaac, Garrett Alice, Loveday Chey, Choi Subin, Torr Beth, Litchfield Kevin, Reid Alison, Huddart Robert, Broderick Peter, Houlston Richard S, Turnbull Clare
Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Department of Clinical Genetics, St George's University Hospitals NHS Foundation Trust, London, UK.
Eur Urol Open Sci. 2025 Feb 13;73:51-59. doi: 10.1016/j.euros.2025.01.015. eCollection 2025 Mar.
Testicular germ cell tumour (TGCT) is the most common cancer in young men, and over half of its high estimated heritability is unexplained. Our objective was to identify rare pathogenic germline variation driving TGCT susceptibility.
This study is a case-control meta-analysis of whole-exome sequencing data from three datasets (Institute of Cancer Research, The Cancer Genome Atlas, and UK Biobank). We retained unrelated male individuals of European ancestry comprising 1435 TGCT cases and 18 284 cancer-free controls. We performed gene-level association testing of protein-truncating variants and nonsynonymous disruptive variants across six candidate gene sets (733 genes) potentially biologically related to TGCT. We then analysed exome wide (19 355 genes) under dominant and recessive models, including X-linked genes.
No individual gene-disease association was identified following multiple testing corrections. However, functional gene-set analyses identified an excess of associations with genes involved in microtubular/ciliary pathways ( = 1.69 × 10). Our study was well powered to detect rare variation of moderate/high effect sizes (odds ratio [OR] ≥5), but power diminished for modest effect sizes (OR <5).
Although this is the largest whole-exome analysis of TGCT to date and first exome-wide examination for recessively acting gene associations, larger studies are required to identify robust associations for individual genes.
We investigated samples from 1435 men with testicular cancer and 18 284 men without cancer to compare the rate of disruptive mutations in 19 355 genes. No evidence of specific genes associated with testicular cancer was discovered, although one gene group showed a strong association. Larger studies are needed to identify individual genes associated with causing testicular cancer.
睾丸生殖细胞肿瘤（TGCT）是年轻男性中最常见的癌症，其高度遗传性中超过一半的原因尚不清楚。我们的目的是确定导致TGCT易感性的罕见致病种系变异。
本研究是对来自三个数据集（癌症研究所、癌症基因组图谱和英国生物银行）的全外显子测序数据进行的病例对照荟萃分析。我们纳入了欧洲血统的无关男性个体，包括1435例TGCT病例和18284例无癌对照。我们对六个可能与TGCT生物学相关的候选基因集（733个基因）中的蛋白质截短变异和非同义破坏性变异进行了基因水平的关联测试。然后，我们在显性和隐性模型下分析了全外显子范围（19355个基因），包括X连锁基因。
经过多重检验校正后，未发现单个基因与疾病的关联。然而，功能基因集分析发现与微管/纤毛途径相关的基因存在过多关联（ = 1.69 × 10）。我们的研究有足够的能力检测中等/高效应大小的罕见变异（优势比[OR]≥5），但对于中等效应大小（OR<5）的检测能力有所下降。
尽管这是迄今为止最大规模的TGCT全外显子分析，也是首次对隐性作用基因关联进行全外显子范围的检查，但仍需要更大规模的研究来确定单个基因的可靠关联。
我们调查了1435名患有睾丸癌的男性和18284名未患癌症的男性的样本，以比较19355个基因中的破坏性突变率。虽然有一组基因显示出强烈关联，但未发现与睾丸癌相关的特定基因的证据。需要更大规模的研究来确定与导致睾丸癌相关的单个基因。
