Somatic Mutation of FAT Family Genes Implicated Superior Prognosis in Patients With Stomach Adenocarcinoma

Abstract

FAT family genes encode protocadherin, which regulates tumor cell proliferation and migration. Although transcriptional levels of FAT family members had been reported in multiple malignant tumors, the association between mutation and prognosis of the FAT family in stomach adenocarcinoma (STAD) has not been investigated. Herein, we performed a multi-omics integrative bioinformatics analysis using genomic and mRNA expression data to explore the role of gene mutations across the FAT family on clinical outcomes of STAD. The results showed that FAT mutations occurred in 174 of 435 (40%) of the samples. Patients with FAT mutations possessed significantly better progression-free survival (P = 0.019) and overall survival (P = 0.034) than those with non-FAT mutations, and FAT mutations exhibited significantly higher tumor mutational burden (TMB) and microsatellite instability. Notably, FAT mutations had a greater effect on somatic single-nucleotide variation than copy number variation and resulted in more abundant DNA damage repair (DDR) mutations. Further investigation demonstrated that FAT mutations contributed to an inflammatory tumor microenvironment (TME), as indicated by significantly increased numbers of activated CD4 and CD8 T cells, and significantly decreased numbers of mast cell, plasmacytoid dendritic cell, type 2 T helper cell, and high expression of immune-promoting genes. Moreover, biological process antigen processing and presentation, DNA replication, and DDR-related pathways were significantly upregulated in patients with FAT mutations. Collectively, FAT mutations significantly improved the survival of patients with STAD by enhancing tumor immunogenicity (e.g., TMB and DDR mutations) and an inflamed TME, indicating that the FAT family might be a potential prognostic and therapeutic biomarker for STAD.

Somatic mutations in FAT cadherin family members constitute an underrecognized subtype of colorectal adenocarcinoma with unique clinicopathologic features

“…Similar to the findings in our study, Wang et al [ 33 ] reported a superior prognosis in gastric adenocarcinoma with FAT family gene mutations. In their study, FAT gene mutations were significantly associated with better progression-free survival and OS, which was likely attributed to the significantly higher tumor mutational burden and an inflamed tumor microenvironment[ 33 ]. Whether the tumor microenvironment plays a similar role in CRC still awaits further investigation.…”

“…FAT1 also promotes actin-mediated cell migration[ 14 , 15 ] and plays a role in epithelial mesenchymal transition[ 16 ]. Somatic mutations of FAT family genes have been detected in different human cancers, including squamous cell carcinoma of the head and neck ( FAT1 , FAT2 and FAT4 )[ 17 - 20 ], breast cancer ( FAT1 )[ 21 ], melanomas ( FAT4 )[ 22 ], leukemia ( FAT1 )[ 23 , 24 ], hepatocellular cancer ( FAT1 , FAT4 )[ 25 , 26 ], esophageal squamous cell carcinoma ( FAT1 )[ 27 - 29 ], pancreatic cancer ( FAT1 , FAT3 and FAT4 )[ 30 , 31 ], and gastric cancer ( FAT4 )[ 32 , 33 ]. Alterations in FAT family genes are associated with tumorigenesis and prognosis.…”

Identification and validation of DNA methylation‐driven gene PCDHB4 as a novel tumor suppressor for glioblastoma diagnosis and prognosis

“…These results demonstrate that the combination of methylation markers and immune infiltration cells may more effectively improve the survival of GBM patients. Moreover, a recent study has found that the FAT family gene in the same family of PCDHB4 can encode protocadherin, and the mutation of this gene enhances tumor immunogenicity, contributes to the inflammatory tumor microenvironment and promotes the activation of CD4 + T cells, thereby improving the prognosis of gastric cancer patients 37 . This may explain the underlying mechanism of the PCDHB4 gene with immune infiltrating CD4 + T cells on the prognosis of GBM patients.…”

“…33,34 In addition, more comprehensive multiomics studies could overcome the low detection of tumor molecules in the blood caused by the blood-brain barrier. 37 This may explain the underlying mechanism of the PCDHB4 gene with immune infiltrating CD4 + T cells on the prognosis of GBM patients.…”