Association of FLG mutation with tumor mutation load and clinical outcomes in patients with gastric cancer

Fu, Yuejun; Liu, Xin; Tian, Yu; Liu, Huilin

doi:10.3389/fgene.2022.808542

Cited by 7 publications

(8 citation statements)

References 49 publications

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“…We also found that FLG is highly mutated and has a signi cant effect on GC prognosis and immune in ltration, including CNV variants and missense mutations. It was partially in concordance with previously published studies [33][34] . In addition, we know that immune cells play a key regulatory role in tumorigenesis and development [35] .…”

Section: Discussionsupporting

confidence: 93%

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Expression Characteristics and Biological Functional Role of FLG in Gastric Cancer

Xia,

Li,

Gao

et al. 2024

Preprint

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Background Filaggrin gene (FLG) plays a fundamental role and is associated with tumor malignant progression and maybe used as a new diagnostic biomarker for many cancers. Nevertheless, the characteristics and biological function in Gastric Cancer (GC) have not yet been elucidated. Thus, we focus on FLG expression, the association with immune infiltration and biological functions in GC. Methods The TCGA and GTEx databases were used to identify the mRNA expression of FLG in GC. We used the HPA database to identify the protein expression of FLG in GC. The Cox regression, Kaplan-Meier and nomogram prediction model were used to analysis the relationship between FLG and survival. We also used the logistic regression to analyze the relationship between FLG expressions and pathological features. FLG genetic modification information was derived from the cBioPortal and the GSCALite database. The relationship between FLG expression and microsatellite instability (MSI), DNA methyltransferases, immune-related genes, tumor mutational burden (TMB) were analyzed. The ESTIMATE and other two methods were evaluated the association between FLG expression and the immune infiltrating cells. The protein-protein interactions between Interacting Genes/ proteins (STRING) were established using the Search Tool. The FLG pathways were analyzed using GO and KEGG enrichment analyses. The ceRNA networks were identified in TCGA database. We performed differential expression of FLG and explored the biological role in tumor malignant progression of GC cells. Results We demonstrated that FLG is up-regulated in GC cells and significantly related with worse prognosis. Genetic alterations may lead to abnormal expression of FLG. Meanwhile, the expression of FLG was strongly correlated with immune characteristics. Moreover, FLG has many molecular functions and participates in many signaling pathways. In the cytology experiments, we found that silencing FLG expression largely inhibits GC cell metastasis via epithelial-mesenchymal transition (EMT) signaling pathway. Conclusion FLG is a novel and useful biomarker for prognosis, immune infiltration and malignant progression of GC.

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Section: Discussionsupporting

confidence: 93%

“…Fu Yicheng indicated that GC patients carrying FLG mutations have signi cantly higher OS and DFS [33] .…”

Section: Discussionmentioning

confidence: 99%

Expression Characteristics and Biological Functional Role of FLG in Gastric Cancer

Xia,

Li,

Gao

et al. 2024

Preprint

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“…FLG also had a lower proportion of mutations in the high-risk group. It has been reported that the FLG mutant group showed a higher mutation load and immunogenicity in gastric cancer, resulting in increased sensitivity of gastric cancer to 24 chemotherapy agents ( 44 ). Our data also showed an association between a higher proportion of FLG mutations and a better response to STAD therapy.…”

Section: Discussionmentioning

confidence: 99%

Characteristic of molecular subtype based on lysosome-associated genes reveals clinical prognosis and immune infiltration of gastric cancer

Hu¹,

Chong²,

et al. 2023

Front. Oncol.

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BackgroundLysosome are involved in nutrient sensing, cell signaling, cell death, immune responses and cell metabolism, which play an important role in the initiation and development of multiple tumors. However, the biological function of lysosome in gastric cancer (GC) has not been revealed. Here, we aim to screen lysosome-associated genes and established a corresponding prognostic risk signature for GC, then explore the role and underlying mechanisms.MethodsThe lysosome-associated genes (LYAGs) were obtained from MSigDB database. Differentially expressed lysosome-associated genes (DE-LYAGs) of GC were acquired based on the TCGA database and GEO database. According to expression profiles of DE-LYAGs, we divided the GC patients into different subgroups and then explored tumor microenvironment (TME) landscape and immunotherapy response in LYAG subtypes using GSVA, ESTIMATE and ssGSEA algorithms. Univariate Cox regression analysis, LASSO algorithm and multivariate Cox regression analysis were adopted to identify the prognostic LYAGs and then establish a risk model for patients with GC. The Kaplan-Meier analysis, Cox regression analysis and ROC analysis were utilized to evaluate the performance of the prognostic risk model. Clinical GC specimens were also used to verify the bioinformatics results by qRT-PCR assay.ResultsThirteen DE-LYAGs were obtained and utilized to distinguish three subtypes in GC samples. Expression profiles of the 13 DE-LYAGs predicted prognosis, tumor-related immunological abnormalities and pathway dysregulation in these three subtypes. Furthermore, we constructed a prognostic risk model for GC based on DEG in the three subtypes. The Kaplan-Meier analysis suggested that higher risk score related to short OS rate. The Cox regression analysis and ROC analysis indicated that risk model had independent and excellent ability in predicting prognosis of GC patients. Mechanistically, a remarkable difference was observed in immune cell infiltration, immunotherapy response, somatic mutation landscape and drug sensitivity. qRT-PCR results showed that compared with corresponding adjacent normal tissues, most screened genes showed significant abnormal expressions and the expression change trends were consistent with the bioinformatics results.ConclusionsWe established a novel signature based on LYAGs which could be served as a prognostic biomarker for GC. Our study might provide new insights into individualized prognostication and precision treatment for GC.

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“…In a prior study, FLG was found to have a higher mutation frequency in prostate cancer and to be associated with an increase in TMB, up-regulation of aberrant immune responses in tumors, and cancer growth than the wild type ( 34 ). The recently published data showed that the FLG-mutant group (FLG-MT) had a greater mutation load and immunogenicity, suggesting that the gene mutation may be a preventative measure in gastric tumor ( 35 ). Other early results suggested that certain atopy-related variations, including the FLG gene may be linked to an increased risk of pancreatic cancer ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical and genetic characteristics in pancreatic cancer from Chinese patients revealed by whole exome sequencing

He,

Huang,

Tang

et al. 2023

Front. Oncol.

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BackgroundPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide, mostly as a result of the absence of early detection and specific treatment solutions. Consequently, identifying mutational profiles and molecular biomarkers is essential for increasing the viability of precision therapy for pancreatic cancer.MethodsWe collected blood and tumor tissue samples from 47 Chinese pancreatic cancer patients and used whole-exome sequencing (WES) to evaluate the genetic landscape.ResultsOur results showed the most frequently somatic alteration genes were KRAS (74.5%), TP53(51.1%), SMAD4 (17%), ARID1A (12.8%), CDKN2A (12.8%), TENM4 (10.6%), TTN (8.5%), RNF43(8.5%), FLG (8.5%) and GAS6 (6.4%) in Chinese PDAC patients. We also found that three deleterious germline mutations (ATM c.4852C>T/p. R1618*, WRN c.1105C>T/p. R369*, PALB2 c.2760dupA/p. Q921Tfs*7) and two novel fusions (BRCA1-RPRML, MIR943 (intergenic)-FGFR3). When compared to the Cancer Genome Atlas (TCGA) database, there is a greater mutation frequency of TENM4 (10.6% vs. 1.6%, p = 0.01), GAS6(6.4% vs. 0.5%, p = 0.035), MMP17(6.4% vs. 0.5%, p = 0.035), ITM2B (6.4% vs. 0.5%, p = 0.035) and USP7 (6.4% vs. 0.5%, p= 0.035) as well as a reduced mutation frequency of SMAD4 (17.0% vs. 31.5%, p = 0.075) and CDKN2A (12.8% vs. 47.3%, p < 0.001) were observed in the Chinese cohort. Among the 41 individuals examined for programmed cell death ligand 1(PD-L1) expression, 15 (36.6%) had positive PD-L1 expression. The median tumor mutational burden (TMB) was found to be 12muts (range, 0124). The TMB index was higher in patients with mutant-type KRAS MUT/TP53 MUT (p < 0.001), CDKN2A (p = 0.547), or SMAD4 (p = 0.064) compared to patients with wild-type KRAS/TP53, CDKN2A, or SMAD4.ConclusionsWe exhibited real-world genetic traits and new alterations in Chinese individuals with cancer of the pancreas, which might have interesting implications for future individualized therapy and medication development.

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Association of FLG mutation with tumor mutation load and clinical outcomes in patients with gastric cancer

Cited by 7 publications

References 49 publications

Expression Characteristics and Biological Functional Role of FLG in Gastric Cancer

Expression Characteristics and Biological Functional Role of FLG in Gastric Cancer

Characteristic of molecular subtype based on lysosome-associated genes reveals clinical prognosis and immune infiltration of gastric cancer

Clinical and genetic characteristics in pancreatic cancer from Chinese patients revealed by whole exome sequencing

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