Gao Lifeng, Wang Xueying, Xu Yixin, Wang Aimin, Zhang Wenjing, Wang Qinghua, Ren Yanfeng
Department of Clinical Laboratory, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong, China.
Key Laboratory of Medicine and Health of Shandong Province, Department of Health Statistics, School of Public Health, Shandong Second Medical University, Weifang, Shandong, China.
Front Genet. 2025 Jul 2;16:1466484. doi: 10.3389/fgene.2025.1466484. eCollection 2025.
FAT atypical cadherin 1 (FAT1) is a well-known tumor regulator that plays a crucial role in multiple cancer signaling pathways. Its mutations have been linked to tumor progression and immune regulation in various cancers, including lung adenocarcinoma (LUAD). In this study, we aim to identify a FAT1 mutation-related transcriptomic risk signature to assess the survival risks and immune status of LUAD patients.
A total of 2528 LUAD samples, which included both gene expression profiles and clinicopathologic data, were collected from 12 datasets. Additionally, two datasets treated with immunotherapies were also included to investigate the therapeutic effects.
We constructed a FAT1 mutation molecular signature based on 9 relevant genes. LUAD patients with low-risk scores demonstrated a more favorable prognosis compared to those with high-risk scores, which is corroborated by 6 additional independent datasets. Further immunological, mutational, and intratumor microbial analyses reveal that increased infiltration of immune effector cells, increased mutational burden, specific mutational signatures (such as age and APOBEC associated), mutations in driver genes (e.g., TP53, KEAP1, NAV3, and SMARCA4), and increased microbial α/β diversities are present in the low-risk LUAD patients. Based on the immunotherapeutic patients, an improved immune checkpoint blockade treatment prognosis and an elevated response rate are also observed in the low-risk signature group.
In summary, Our identified FAT1 mutation-related risk signature shows potential for assessing LUAD clinical outcomes, tumor immunogenicity, and immunotherapy effectiveness, providing valuable insights for LUAD clinical practice.
FAT非典型钙黏蛋白1（FAT1）是一种著名的肿瘤调节因子，在多种癌症信号通路中起关键作用。其突变与包括肺腺癌（LUAD）在内的多种癌症的肿瘤进展和免疫调节有关。在本研究中，我们旨在识别一种与FAT1突变相关的转录组风险特征，以评估LUAD患者的生存风险和免疫状态。
从12个数据集中收集了总共2528个LUAD样本，这些样本包括基因表达谱和临床病理数据。此外，还纳入了两个接受免疫治疗的数据集以研究治疗效果。
我们基于9个相关基因构建了FAT1突变分子特征。低风险评分的LUAD患者与高风险评分的患者相比，预后更有利，这在另外6个独立数据集中得到了证实。进一步的免疫学、突变和肿瘤内微生物分析表明，低风险LUAD患者中免疫效应细胞浸润增加、突变负担增加、特定的突变特征（如与年龄和载脂蛋白B mRNA编辑酶催化多肽样蛋白相关）、驱动基因（如TP53、KEAP1、NAV3和SMARCA4）突变以及微生物α/β多样性增加。基于接受免疫治疗的患者，在低风险特征组中也观察到免疫检查点阻断治疗预后改善和反应率提高。
总之，我们识别出的与FAT1突变相关的风险特征显示出评估LUAD临床结局、肿瘤免疫原性和免疫治疗有效性的潜力，为LUAD临床实践提供了有价值的见解。
