FAT2 mutation is associated with better prognosis and responsiveness to immunotherapy in uterine corpus endometrial carcinoma

Abstract

Background: Uterine corpus endometrial carcinoma (UCEC) ranks sixth among malignant tumors in women and the mortality is still rising. FAT2 gene has been considered to be related to the survival and prognosis of some certain diseases in previous studies, but the FAT2 mutation status in UCEC and its prognostic value has been rarely studied. Hence, the purpose of our study was to explore the role of FAT2 mutations for predicting prognosis and responsiveness to immunotherapy in patients with UCEC.

Methods: UCEC samples from the Cancer Genome Atlas database were analyzed. We evaluated the impact of FAT2 gene mutation status and clinicopathological characteristics on the prognosis of UCEC patients and used univariate and multivariate Cox analysis risk scores to independently predict patient overall survival (OS). Tumor mutation burden (TMB) values of the FAT2 mutant and non-mutant groups were computed by Wilcoxon rank sum test. The correlation of FAT2 mutation and half maximal inhibitory concentration (IC50) values of various anticancer drugs was analyzed. Gene Ontology data and Gene Set Enrichment Analysis (GSEA) were employed to examine the differential expression of genes between the two groups. Finally, a single-sample GSEA arithmetic was utilized to measure the abundance of tumor-infiltrating immune cells in UCEC patients.

Results: FAT2 mutations suggested better OS (p < 0.001) and disease-free survival (DFS) (p = 0.007) in UCEC. The IC50 values of 18 anticancer drugs were upregulated in FAT2 mutation patients (p < 0.05). The TMB and microsatellite instability values of patients with FAT2 mutations were significantly higher (p < 0.001). Next, the Kyoto Encyclopedia of Genes and Genomes functional analysis and GSEA revealed the potential mechanism of FAT2 mutation on the tumorigenesis and progression of UCEC. In addition, in reference to the UCEC microenvironment, the infiltration levels of activated CD4/CD8 T cells (p < 0.001/p = 0.001) and plasmacytoid dendritic cells (p = 0.006) were upregulated in the non-FAT2 mutation group, and Type 2 T helper cells (p = 0.001) were downregulated in the FAT2 mutation group.

Conclusions: UCEC patients with FAT2 mutations have better prognosis and are more likely to respond to immunotherapy. FAT2 mutation may be a valuable predictor for prognosis and responsiveness to immunotherapy in UCEC patients.

Keywords: FAT2 mutation; immunotherapy; prognosis; uterine corpus endometrial carcinoma.