scholarly journals Combined Simplified Molecular Classification of Gastric Adenocarcinoma, Enhanced by Lymph Node Status: An Integrative Approach

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3722
Author(s):  
Till Daun ◽  
Ronny Nienhold ◽  
Aino Paasinen-Sohns ◽  
Angela Frank ◽  
Melanie Sachs ◽  
...  
Keyword(s):  
Lymph Node ◽  
Gastric Adenocarcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Molecular Classification ◽  
The Cancer Genome Atlas ◽  
Integrative Approach ◽  
Lymph Node Status ◽  
Mesenchymal Transition ◽  
Barr Virus

Gastric adenocarcinoma (GAC) is a heterogeneous disease and at least two major studies have recently provided a molecular classification for this tumor: The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ARCG). Both classifications quote four molecular subtypes, but these subtypes only partially overlap. In addition, the classifications are based on complex and cost-intensive technologies, which are hardly feasible for everyday practice. Therefore, simplified approaches using immunohistochemistry (IHC), in situ hybridization (ISH) as well as commercially available next generation sequencing (NGS) have been considered for routine use. In the present study, we screened 115 GAC by IHC for p53, MutL Homolog 1 (MLH1) and E-cadherin and performed ISH for Epstein–Barr virus (EBV). In addition, sequencing by NGS for TP53 and tumor associated genes was performed. With this approach, we were able to define five subtypes of GAC: (1) Microsatellite Instable (MSI), (2) EBV-associated, (3) Epithelial Mesenchymal Transition (EMT)-like, (4) p53 aberrant tumors surrogating for chromosomal instability and (5) p53 proficient tumors surrogating for genomics stable cancers. Furthermore, by considering lymph node metastasis in the p53 aberrant GAC, a better prognostic stratification was achieved which finally allowed us to separate the GAC highly significant in a group with poor and good-to-intermediate prognosis, respectively. Our data show that molecular classification of GAC can be achieved by using commercially available assays including IHC, ISH and NGS. Furthermore, we present an integrative workflow, which has the potential to overcome the uncertainty resulting from discrepancies from existing classification schemes.

ASAP1 promotes tumor progression and angiogenesis and independently predicts poor prognosis and lymph node metastasis of gastric cancer

2019 ◽  
Author(s):  
Hongyu Gao ◽  
Ling Qin ◽  
Huawen Shi ◽  
Hongfeng Zhang ◽  
Chunfeng Li ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Node Metastasis ◽  
Tumor Cell Motility

Abstract Background: Although ArfGAP with SH3 Domain, Ankyrin Repeat and PH Domain 1(ASAP1) is involved in the development of various malignancies, its clinical significance and mechanism in gastric cancer (GC) remains unclear.Methods: The effects of ASAP1 on tumor progression, angiogenesis, and epithelial-mesenchymal transition were evaluated in vitro. The effects of ASAP1 on tumor growth and angiogenesis were also explored in vivo. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were used to gather ASAP1 expression data.Results: It showed that ASAP1 expression strongly correlated with the TNM stage (P < 0.0001) and lymph node metastasis (P < 0.0001). Multivariate analyses indicated that ASAP1 overexpression (P < 0.0001) was an independent predictor for overall survival in patients with GC. Moreover, the results revealed that ASAP1 overexpression was independently related to lymph node metastasis (P = 0.0001). ASAP1 knockdown inhibited tumor cell motility, migration, invasion, and angiogenesis, which was accompanied with the downregulation of metastatic and angiogenic biomarkers. Furthermore, ASAP1 inhibition resulted in the simultaneous downregulation of mesenchymal markers and upregulation of epithelial markers. In addition, ASAP1 promoted tumor growth and angiogenesis in the xenograft mice model. The combined datasets (TCGA and GEO) suggested that ASAP1 was associated with malignant behavior of tumor and tumor invasion, metastasis, and angiogenesis.Conclusion: To our knowledge, our study is the first to reveal that ASAP1 promotes tumor progression and angiogenesis, and indicates a prognostic potential in GCs.

scholarly journals A Molecular Stratification of Chilean Gastric Cancer Patients with Potential Clinical Applicability

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1863
Author(s):  
Mauricio P. Pinto ◽  
Miguel Córdova-Delgado ◽  
Ignacio N. Retamal ◽  
Matías Muñoz-Medel ◽  
M. Loreto Bravo ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Latin American ◽  
Epithelial To Mesenchymal Transition ◽  
Low Cost ◽  
Molecular Classification ◽  
The Cancer Genome Atlas ◽  
Mesenchymal Transition ◽  
Barr Virus ◽  
Clinical Applicability ◽  
Stratification System

Gastric cancer (GC) is a complex and heterogeneous disease. In recent decades, The Cancer Genome Atlas (TCGA) and the Asian Cancer Research Group (ACRG) defined GC molecular subtypes. Unfortunately, these systems require high-cost and complex techniques and consequently their impact in the clinic has remained limited. Additionally, most of these studies are based on European, Asian, or North American GC cohorts. Herein, we report a molecular classification of Chilean GC patients into five subtypes, based on immunohistochemical (IHC) and in situ hybridization (ISH) methods. These were Epstein–Barr virus positive (EBV+), mismatch repair-deficient (MMR-D), epithelial to mesenchymal transition (EMT)-like, and accumulated (p53+) or undetected p53 (p53−). Given its lower costs this system has the potential for clinical applicability. Our results confirm relevant molecular alterations previously reported by TCGA and ACRG. We confirm EBV+ and MMR-D patients had the best prognosis and could be candidates for immunotherapy. Conversely, EMT-like displayed the poorest prognosis; our data suggest FGFR2 or KRAS could serve as potential actionable targets for these patients. Finally, we propose a low-cost step-by-step stratification system for GC patients. To the best of our knowledge, this is the first Latin American report on a molecular classification for GC. Pending further validation, this stratification system could be implemented into the routine clinic

scholarly journals Association of MALAT1 and PVT1 Variants, Expression Profiles and Target miRNA-101 and miRNA-186 with Colorectal Cancer: Correlation with Epithelial-Mesenchymal Transition

2021 ◽  
Vol 22 (11) ◽  
pp. 6147
Author(s):  
Abdullah F. Radwan ◽  
Olfat G. Shaker ◽  
Noha A. El-Boghdady ◽  
Mahmoud A. Senousy
Keyword(s):  
Colorectal Cancer ◽  
Lymph Node ◽  
Epithelial Mesenchymal Transition ◽  
Expression Profiles ◽  
Tumor Stage ◽  
Lymph Node Status ◽  
Mesenchymal Transition ◽  
Logistic Analysis ◽  
Diagnostic Potential ◽  
E Cadherin

The influence of PVT1 and MALAT1 variants on colorectal cancer (CRC) susceptibility and their impact on PVT1/miRNA-186/epithelial-mesenchymal transition (EMT) and MALAT1/miRNA-101/EMT axes in CRC are unknown. We investigated the influence of PVT1 rs13255292 and MALAT1 rs3200401 on the risk of CRC and adenomatous polyps (AP), their impact on the long noncoding RNAs PVT1 and MALAT1 expression and their target miRNA-186, miRNA-101/E-cadherin pathways, along with their potential as early CRC biomarkers. Overall, 280 individuals were recruited: 140 patients with CRC, 40 patients with AP, and 100 healthy volunteers. Genotyping and serum expression profiles were assessed using qPCR. The EMT biomarker, E-cadherin, was measured by ELISA. rs3200401 was associated with increased CRC risk, whereas rs13255292 was protective. Serum PVT1 and MALAT1 were upregulated in CRC and AP patients versus healthy controls, whereas, miRNA-186, miRNA-101 and E-cadherin were downregulated in CRC versus non-CRC groups. MALAT1 showed superior diagnostic potential for CRC and predicted CRC risk among non-CRC groups in the multivariate logistic analysis. PVT1, MALAT1, miRNA-186 and miRNA-101 levels were correlated with E-cadherin, tumor stage, lymph node and distant metastasis. E-cadherin was lost in metastatic vs. non-metastatic CRC. rs3200401CC genotype carriers showed higher E-cadherin levels than CC + CT carriers. rs3200401 was correlated with lymph node status. For the first time, rs13255292 and rs3200401 are potential genetic CRC predisposition markers, with rs3200401 possibly impacting the EMT process. Serum PVT1, MALAT1, miRNA-186 and miRNA-101 are novel non-invasive diagnostic biomarkers that could improve the clinical outcome of CRC.

scholarly journals Identification and Validation of an Individualized EMT-Related Prognostic Risk Score Formula in Gastric Adenocarcinoma Patients

2020 ◽  
Vol 2020 ◽  
pp. 1-15 ◽  
Author(s):  
Deyu Zhang ◽  
Siran Zhou ◽  
Bingrong Liu
Keyword(s):  
Gastric Adenocarcinoma ◽  
Risk Score ◽  
Prognostic Value ◽  
Cox Regression ◽  
Epithelial Mesenchymal Transition ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Gastrointestinal Malignancy ◽  
Mesenchymal Transition ◽  
Cancer Genome Atlas

Background. The epithelial-mesenchymal transition (EMT) is a pivotal process for fibrotic disease, embryonic development, and wound healing. Moreover, some evidence has proven that the disorder of EMT also plays an important role in carcinogenesis, especially invasion and metastasis of various tumors (Ritchie et al., 2015). Additionally, gastric adenocarcinoma (GAC) is a common gastrointestinal malignancy which is the fourth most commonly diagnosed tumor. Our study is aimed at identifying the prognostic value of EMT-related genes in gastric adenocarcinoma. Methods. Firstly, high-throughput and clinical data were downloaded from The Cancer Genome Atlas (TCGA) database. 99 differentially expressed EMT-related genes (ERGs) were obtained in these gastric adenocarcinoma data. Secondly, GO and KEGG enrichment analyses show that EMT may promote gastric carcinogenesis. Next, 10 ERGs associated with prognosis of gastric adenocarcinoma patients are screened out by univariate Cox regression, and 6 pivotal prognostic ERGs (MMP8, MMP11, TFDP3, MYB, F2, and CNTN1) are identified through multivariate Cox regression. These 6 genes are confirmed with significant prognostic value in gastric adenocarcinoma through overall survival (OS) analysis. Finally, a risk score formula is constructed and tested in another gastric adenocarcinoma cohort from GEO. Results. 99 differentially expressed EMT-related genes (ERGs) and their enriched pathways are identified. 10 ERGs are strongly related to the prognosis of GAC patients. A risk score formula of 6 prognosis-related ERGs used to predict the prognosis of gastric adenocarcinoma patients is identified and tested (risk score=0.448115∗expression value of MMP8+0.378892∗expression value of MMP11−0.3226∗expression value of MYB+1.322812∗expression value of TFDP3+0.325063∗expression value of F2+0.334197∗expression value of CNTN1). Conclusion. This study provides a potential prognostic signature for predicting prognosis of gastric adenocarcinoma patients and molecular insights of EMT in gastric adenocarcinoma, and the formula focusing on the prognosis of gastric adenocarcinoma can be effective.

scholarly journals CHN1 promotes epithelial–mesenchymal transition via the Akt/GSK-3β/Snail pathway in cervical carcinoma

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Haoqi Zhao ◽  
Lan Wang ◽  
Shufang Wang ◽  
Xihua Chen ◽  
Min Liang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lymph Node ◽  
Signaling Pathway ◽  
Cervical Carcinoma ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Xenograft Tumor ◽  
Mesenchymal Transition ◽  
Gsk 3Β ◽  
Related Proteins

Abstract Background Metastasis and invasion are crucial in determining the mortality of cervical carcinoma (CC) patients. The epithelial–mesenchymal transition (EMT) is now a universal explanation for the mechanisms of tumor metastasis. Α-chimeric protein (α-chimaerin, CHN1) plays an important role in the regulation of signal transduction and development. However, the molecular regulatory relationships between CHN1 and CC progression in relation to EMT have not yet been identified. Methods The expression of CHN1 in CC tissues, adjacent tissues, and lymph node metastases from CC patients was detected by immunohistochemistry. Upregulation and knockdown of CHN1 were achieved by transfection of CC cells. The effect of CHN1 on cell proliferation was determined by CCK-8 and plate clone formation assays. Changes in migration and invasion capabilities were evaluated using scratch migration and transwell invasion assays. The effect of CHN1 overexpression and interference on xenograft tumor growth was determined by tumor weight and pathological analyses. The expression of EMT-related mRNAs was measured by qRT-PCR in transfected CC cells. EMT-related proteins and Akt/GSK-3β/Snail signaling pathway-related proteins were also evaluated by western blotting. Results CHN1 was overexpressed in CC tissues and was associated with lymph node metastasis and low survival in CC patients. Overexpression of CHN1 promoted cell proliferation, migration, and invasion in CC cells. In contrast, silencing of CHN1 inhibited these phenomena. Overexpression of CHN1 promoted tumor formation in an in vivo xenograft tumor mouse model, with increased tumor volumes and weights. In addition, CHN1 induced the expression of EMT-related transcription factors, accompanied by the decreased expression of epithelial markers and increased expression of mesenchymal markers. The Akt/GSK-3β/Snail signaling pathway was activated by overexpression of CHN1 in vitro, and activation of this pathway was inhibited by the signaling pathway inhibitor LY294002. Conclusion These results suggest that CHN1 promotes the development and progression of cervical carcinoma via the Akt/GSK-3β/Snail pathway by inducing EMT.

scholarly journals A novel prognostic model based on epithelial-mesenchymal transition-related genes predicts patient survival in gastric cancer

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Wanting Song ◽  
Yi Bai ◽  
Jialin Zhu ◽  
Fanxin Zeng ◽  
Chunmeng Yang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Risk Model ◽  
Cox Regression ◽  
Epithelial Mesenchymal Transition ◽  
Risk Groups ◽  
The Cancer Genome Atlas ◽  
Critical Function ◽  
Mesenchymal Transition ◽  
Patient Prognosis

Abstract Background Gastric cancer (GC) represents a major malignancy and is the third deathliest cancer globally. Several lines of evidence indicate that the epithelial-mesenchymal transition (EMT) has a critical function in the development of gastric cancer. Although plentiful molecular biomarkers have been identified, a precise risk model is still necessary to help doctors determine patient prognosis in GC. Methods Gene expression data and clinical information for GC were acquired from The Cancer Genome Atlas (TCGA) database and 200 EMT-related genes (ERGs) from the Molecular Signatures Database (MSigDB). Then, ERGs correlated with patient prognosis in GC were assessed by univariable and multivariable Cox regression analyses. Next, a risk score formula was established for evaluating patient outcome in GC and validated by survival and ROC curves. In addition, Kaplan-Meier curves were generated to assess the associations of the clinicopathological data with prognosis. And a cohort from the Gene Expression Omnibus (GEO) database was used for validation. Results Six EMT-related genes, including CDH6, COL5A2, ITGAV, MATN3, PLOD2, and POSTN, were identified. Based on the risk model, GC patients were assigned to the high- and low-risk groups. The results revealed that the model had good performance in predicting patient prognosis in GC. Conclusions We constructed a prognosis risk model for GC. Then, we verified the performance of the model, which may help doctors predict patient prognosis.

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