Prognostic value and antitumor immune response elicited by FAT3 and LRP1B co-mutation in endometrial cancer

Abstract FAT3 and LRP1B, two tumor suppressor genes with high mutation frequency in multiple cancer types, have been linked to prognosis and prediction of immunotherapy response in a few previous studies, but their clinical significance in endometrial cancer (EC) has been relatively poorly studied. In this study, based on a cohort of 502 EC samples, we performed a comprehensive analysis of its multidimensional data types including genomic, transcriptomic, and clinical information. We observed that the incidences of FAT3 and LRP1B mutations in EC patients were 19.52% and 19.32%, respectively, and there was a tendency for co-occurrence between mutations of these two genes, with a co-mutation frequency of 11.16%. FAT3 and LRP1B co-mutation was not only associated with age, weight, tumor type, and new neoplasm event, but also defined a dataset with prominently increased mutational burden, decreased tumor aneuploidy, and specially enriched in microsatellite instability high (MSI-H). Furthermore, the co-mutation subgroup manifested increased expression of cytotoxic T-cell markers, effector cytokines, and immune checkpoints, 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. More strikingly, EC patients with FAT3 and LRP1B co-mutation possessed significantly prolonged progression free survival (PFS) and overall survival (OS). In conclusion, this research provides evidence that FAT3 and LRP1B co-mutation may serve as a potential prognostic and predictive biomarker of antitumor immunity activation in endometrial cancer.