目的:FAT3和LRP1B是两种在多种癌症类型中具有高突变频率的肿瘤抑制基因,我们试图研究这两个基因在EC中的预后和免疫学意义.
方法:基于502个EC样本的队列,我们对其多维数据类型进行了全面分析,包括基因组,转录组,和临床信息,系统讨论了FAT3和LRP1B共突变对抗肿瘤免疫应答和预后的潜在影响.
结果:我们观察到FAT3和LRP1B共突变不仅被定义为TMB显著增加的数据集,肿瘤非整倍体减少,并特别富含MSI-H亚型,但也表现出免疫相关标志物的表达增加,尤其是PD-L1水平的排他性上调和更高的PD-L1+/CD8A+比例。进一步的分析集中在淋巴细胞浸润和途径富集上,探索了微环境的免疫细胞组成和影响肿瘤发展的潜在分子机制。此外,FAT3和LRP1B共突变的EC患者PFS和OS显著延长,共变状态被证明是独立的预后因素。通过将共突变与临床特征相结合,构建了具有高预测性能的列线图。更引人注目的是,合并突变的ECMSI-H患者的预后明显改善,他们的存活率达到了与POLE亚型一致的水平。
结论:在子宫内膜癌中,FAT3和LRP1B的共突变不仅导致免疫状态的激活,但也代表了一个预后改善的亚组,特别是在MSI-H亚型中。
FAT3 and
LRP1B are two tumor suppressor genes with high mutation frequency in multiple cancer types, we sought to investigate the prognostic and immunological significance of these two genes in EC.
Based on a cohort of 502 EC samples, we conducted a comprehensive analysis of its multidimensional data types including genomic, transcriptomic, and clinical information, the potential impact of FAT3 and
LRP1B co-mutation on antitumor immune response and prognosis were systematically discussed.
We observed that FAT3 and
LRP1B co-mutation was not only defined a dataset with prominently increased TMB, decreased tumor aneuploidy, and specially enriched in MSI-H subtype, but also manifested increased expression of immune-related markers, especially exclusive upregulation of PD-L1 levels and higher PD-L1+/CD8A+ proportion. Further analysis focused on lymphocyte infiltration and pathway enrichment explored the immune cell composition of the microenvironment and underlying molecular mechanisms affecting tumor development. Furthermore, EC patients with FAT3 and
LRP1B co-mutation possessed significantly prolonged PFS and OS, and the co-mutation status was proved to be an independent prognostic factor. And a nomogram with high predictive performance was constructed by incorporating co-mutation with clinical features. More strikingly, the prognosis of MSI-H patients in EC with co-mutation was significantly improved, and their survival reached a level consistent with the POLE subtype.
In endometrial cancer, co-mutation of FAT3 and
LRP1B not only leads to activation of the immune state, but also represents a subgroup with an improved prognosis, particularly in the MSI-H subtype.