Wang Jing, Luo Ningning, Han Tiantian, Yin Xiangyu, Wang Guangyu
Department of Pathology, Jining No.1 People's Hospital, Jining, China.
The Medical Department, Jiangsu Simcere Diagnostics Co, Ltd, Nanjing Simcere Medical Laboratory Science Co, Ltd, The State Key Laboratory of Neurology and Oncology Drug Development, Nanjing, China.
JCO Precis Oncol. 2025 Sep;9:e2500435. doi: 10.1200/PO-25-00435. Epub 2025 Sep 4.
Germ cell tumors (GCTs) are a heterogeneous group of neoplasms that predominantly affect adolescents and young adults. Notably, geographical disparities in GCT incidence exist, with higher rates observed in East Asia. Although numerous studies have established links between heterozygous germline mutations in Fanconi anemia (FA) genes and the development of certain human cancers, the association between germline pathogenic or likely pathogenic (P/LP) variants in FA genes and the relative risk of developing GCTs remains incompletely characterized.
In this study, we used next-generation sequencing (NGS) to investigate the genetic susceptibility patterns of Chinese patients with GCTs for the first time. We investigated the association between germline P/LP variants in FA-related genes and the risk of developing GCTs. Furthermore, we compared clinical characteristics, mutational landscape, and mutational signatures between patients with and without germline P/LP variants in FA-related genes.
We identified heterozygous germline P/LP variants in FA-related genes in 12.12% (8/66) of patients with GCTs, involving , , , , and . Our findings demonstrate a significant association between a subset of FA genes and an increased relative risk of GCTs, indicating a role for these variants in GCT predisposition. Furthermore, patients harboring these FA gene variants exhibited a higher number of mutations, increased propensity for gene fusions, and demonstrated a greater degree of genomic instability.
These results elucidate the contribution of FA-related germline variants to GCT pathogenesis and advance our understanding of the genetic determinants influencing GCT relative risk. This research provides a basis for developing more effective screening strategies, personalized treatment approaches, and improved patient management strategies for GCTs.
生殖细胞肿瘤（GCTs）是一组异质性肿瘤，主要影响青少年和年轻成年人。值得注意的是，GCT发病率存在地理差异，东亚地区的发病率较高。尽管众多研究已确立范可尼贫血（FA）基因的杂合种系突变与某些人类癌症发生之间的联系，但FA基因中的种系致病性或可能可能致病性或可能致病性（P/LP）变异与发生GCT的相对风险之间的关联仍未完全明确。
在本研究中，我们首次使用二代测序（NGS）来调查中国GCT患者的遗传易感性模式。我们研究了FA相关基因中的种系P/LP变异与发生GCT风险之间的关联。此外，我们比较了FA相关基因中存在和不存在种系P/LP变异的患者之间的临床特征、突变格局和突变特征。
我们在12.12%（8/66）的GCT患者中鉴定出FA相关基因中的杂合种系P/LP变异，涉及 、 、 、 及 。我们的研究结果表明，一部分FA基因与GCT相对风险增加之间存在显著关联，表明这些变异在GCT易感性中起作用。此外，携带这些FA基因变异的患者表现出更多的突变、更高的基因融合倾向，并表现出更大程度的基因组不稳定性。
这些结果阐明了FA相关种系变异对GCT发病机制的贡献，并增进了我们对影响GCT相对风险的遗传决定因素的理解。本研究为制定更有效的筛查策略、个性化治疗方法以及改善GCT患者管理策略提供了依据。
