Mutations in LRRC50 Predispose Zebrafish and Humans to Seminomas

Seminoma is a subclass of human testicular germ cell tumors (TGCT), the most frequently observed cancer in young men with a rising incidence. Here we describe the identification of a novel gene predisposing specifically to seminoma formation in a vertebrate model organism. Zebrafish carrying a heterozygous nonsense mutation in Leucine-Rich Repeat Containing protein 50 (lrrc50 also called dnaaf1), associated previously with ciliary function, are found to be highly susceptible to the formation of seminomas. Genotyping of these zebrafish tumors shows loss of heterozygosity (LOH) of the wild-type lrrc50 allele in 44.4% of tumor samples, correlating with tumor progression. In humans we identified heterozygous germline LRRC50 mutations in two different pedigrees with a family history of seminomas, resulting in a nonsense Arg488* change and a missense Thr590Met change, which show reduced expression of the wild-type allele in seminomas. Zebrafish in vivo complementation studies indicate the Thr590Met to be a loss-of-function mutation. Moreover, we show that a pathogenic Gln307Glu change is significantly enriched in individuals with seminoma tumors (13% of our cohort). Together, our study introduces an animal model for seminoma and suggests LRRC50 to be a novel tumor suppressor implicated in human seminoma pathogenesis.精原细胞瘤（seminoma）是人类睾丸生殖细胞肿瘤（testicular germ cell tumors, TGCT）的一个亚型，该类肿瘤是年轻男性中最常见的恶性肿瘤，且发病率呈逐年上升趋势。本研究报道了一种可在脊椎动物模型中特异性诱发精原细胞瘤形成的新基因的鉴定结果。研究发现，携带富含亮氨酸重复序列蛋白50（Leucine-Rich Repeat Containing protein 50，LRRC50，又称dnaaf1）杂合无义突变的斑马鱼，极易罹患精原细胞瘤——该基因此前被证实与纤毛功能相关。对斑马鱼肿瘤样本进行基因分型后发现，44.4%的肿瘤样本中出现了野生型lrrc50等位基因的杂合性缺失（loss of heterozygosity, LOH），且该现象与肿瘤进展密切相关。在人类群体中，我们在两个具有精原细胞瘤家族史的家系中鉴定出LRRC50的杂合生殖系突变，分别导致无义突变Arg488*（精氨酸488突变为终止密码子）和错义突变Thr590Met（苏氨酸590突变为甲硫氨酸），上述突变会使精原细胞瘤中野生型等位基因的表达水平显著降低。斑马鱼体内互补实验证实，Thr590Met属于功能丧失型突变。此外，我们发现致病性突变Gln307Glu（谷氨酰胺307突变为谷氨酸）在精原细胞瘤患者中显著富集（本研究队列中占比达13%）。综上，本研究建立了精原细胞瘤的动物模型，并提示LRRC50是一种参与人类精原细胞瘤发病机制的新型肿瘤抑制基因。