Prognostic and Immunological Role of FAT Family Genes in Non-Small Cell Lung Cancer

Feng, Zhenxing; Yin, Yan; Liu, Bin; Zheng, Yafang; Shi, Dongsheng; Zhang, Hong; Qin, Jianwen

doi:10.1177/10732748221076682

Cited by 14 publications

(15 citation statements)

References 57 publications

(70 reference statements)

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“…Interestingly, mutations in these junction proteins show high neoantigen potentials, which is correlated with T-lymphocyte infiltration and better clinical outcomes after immune therapy with immune checkpoint inhibitors (ICIs). Similar immune regulatory effects have also been reported in other studies, namely, that somatic mutations in atypical cadherin proteins, e.g., members of the FAT family, can promote cancer development, while patients with such mutations usually show higher mutation burdens, longer survival times, or better therapeutic outcomes by ICI therapy than patients without [ 116 , 117 , 118 ].…”

Section: Regulation Of Immune Tme By Mutations In Cytoskeleton-associ...supporting

confidence: 77%

Alterations of Cytoskeleton Networks in Cell Fate Determination and Cancer Development

et al. 2022

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Cytoskeleton proteins have been long recognized as structural proteins that provide the necessary mechanical architecture for cell development and tissue homeostasis. With the completion of the cancer genome project, scientists were surprised to learn that huge numbers of mutated genes are annotated as cytoskeletal or associated proteins. Although most of these mutations are considered as passenger mutations during cancer development and evolution, some genes show high mutation rates that can even determine clinical outcomes. In addition, (phospho)proteomics study confirms that many cytoskeleton-associated proteins, e.g., β-catenin, PIK3CA, and MB21D2, are important signaling mediators, further suggesting their biofunctional roles in cancer development. With emerging evidence to indicate the involvement of mechanotransduction in stemness formation and cell differentiation, mutations in these key cytoskeleton components may change the physical/mechanical properties of the cells and determine the cell fate during cancer development. In particular, tumor microenvironment remodeling triggered by such alterations has been known to play important roles in autophagy, metabolism, cancer dormancy, and immune evasion. In this review paper, we will highlight the current understanding of how aberrant cytoskeleton networks affect cancer behaviors and cellular functions through mechanotransduction.

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Section: Regulation Of Immune Tme By Mutations In Cytoskeleton-associ...supporting

confidence: 77%

Alterations of Cytoskeleton Networks in Cell Fate Determination and Cancer Development

et al. 2022

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“…As shown in Supplementary Figure 4 , FAT mutations significantly prolonged PFS and OS of patients with STAD or uterine corpus endometrial carcinoma and were detrimental to survival in patients with esophageal carcinoma, adrenocortical carcinoma, kidney renal papillary cell carcinoma, pancreatic adenocarcinoma, or pheochromocytoma and paraganglioma, suggesting FAT mutations were related to several tumors and might differentially affect tumor growth by regulating different biological processes. Recently, Feng et al discover that FAT family genes are potential prognostic and immunological biomarkers and correlate with response to ICIs in non-small cell lung cancer ( 50 ), demonstrating that FAT family may also play roles in STAD immunotherapy. Another study reveals NFκB (RelA)/RelA/p65 as the transcriptional regulator of FAT1 gene in GBM cells ( 51 ), suggesting that transcriptional regulators might control the downstream signaling of FAT genes.…”

Section: Discussionmentioning

confidence: 99%

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

Wang¹,

Cui²,

Li³

et al. 2022

Front. Med.

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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.

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“…In NSCLC cohort treated with ICI, FAT2 mutations may predict better clinical beneficial response and longer progression‐free survival. 17 Based on the above information, we infer that FAT2 may get involved in the tumorigenesis, progression, and treatment of UCEC.…”

Section: Introductionmentioning

confidence: 89%

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

et al. 2022

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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.

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Prognostic and Immunological Role of FAT Family Genes in Non-Small Cell Lung Cancer

Cited by 14 publications

References 57 publications

Alterations of Cytoskeleton Networks in Cell Fate Determination and Cancer Development

Alterations of Cytoskeleton Networks in Cell Fate Determination and Cancer Development

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

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

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