Quantitative Biomedical Research Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Population & Data Sciences, Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nat Commun. 2023 May 6;14(1):2636. doi: 10.1038/s41467-023-38378-9.
Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0-24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.
生殖细胞肿瘤（GCTs）是发生于婴儿、儿童、青少年和成人睾丸、卵巢和性腺外部位的肿瘤。青春期后（Ⅱ型）恶性 GCT 可能表现为精原细胞瘤、非精原细胞瘤或混合组织学类型。相比之下，青春期前（Ⅰ型）GCT 仅限于（良性）畸胎瘤和（恶性）卵黄囊瘤（YST）。流行病学和分子数据表明，青春期前和青春期后 GCT 的发生机制不同。目前尚缺乏儿童和青少年Ⅰ型和Ⅱ型 GCT 基因组景观的专门研究。在这里，我们对 0-24 岁年龄范围内的颅外 GCT 进行了综合基因组分析。WNT 通路的激活，包括体细胞突变、拷贝数改变和差异启动子甲基化，是儿童、青少年和年轻成人 GCT 的一个显著特征，与不良临床结局相关。重要的是，我们发现小分子 WNT 抑制剂可以在体外和体内抑制 GCT 细胞。这些结果强调了 WNT 通路信号在所有年龄段 GCT 中的重要性，并为未来开发这些癌症的靶向治疗奠定了基础。
