scholarly journals Analysis of Gastric Cancer Transcriptome Allows the Identification of Histotype Specific Molecular Signatures With Prognostic Potential

2021 ◽  
Vol 11 ◽  
Author(s):  
Adriana Carino ◽  
Luigina Graziosi ◽  
Silvia Marchianò ◽  
Michele Biagioli ◽  
Elisabetta Marino ◽  
...  

Gastric cancer is the fifth most common malignancy but the third leading cause of cancer-associated mortality worldwide. Therapy for gastric cancer remain largely suboptimal making the identification of novel therapeutic targets an urgent medical need. In the present study we have carried out a high-throughput sequencing of transcriptome expression in patients with gastric cancers. Twenty-four patients, among a series of 53, who underwent an attempt of curative surgery for gastric cancers in a single center, were enrolled. Patients were sub-grouped according to their histopathology into diffuse and intestinal types, and the transcriptome of the two subgroups assessed by RNAseq analysis and compared to the normal gastric mucosa. The results of this investigation demonstrated that the two histopathology phenotypes express two different patterns of gene expression. A total of 2,064 transcripts were differentially expressed between neoplastic and non-neoplastic tissues: 772 were specific for the intestinal type and 407 for the diffuse type. Only 885 transcripts were simultaneously differentially expressed by both tumors. The per pathway analysis demonstrated an enrichment of extracellular matrix and immune dysfunction in the intestinal type including CXCR2, CXCR1, FPR2, CARD14, EFNA2, AQ9, TRIP13, KLK11 and GHRL. At the univariate analysis reduced levels AQP9 was found to be a negative predictor of 4 years survival. In the diffuse type low levels CXCR2 and high levels of CARD14 mRNA were negative predictors of 4 years survival. In summary, we have identified a group of genes differentially regulated in the intestinal and diffuse histotypes of gastric cancers with AQP9, CARD14 and CXCR2 impacting on patients’ prognosis, although CXCR2 is the only factor independently impacting overall survival.

2021 ◽  
Author(s):  
Adriana Carino ◽  
Luigina Graziosi ◽  
Silvia Marchianò ◽  
Michele Biagioli ◽  
Elisabetta Marino ◽  
...  

AbstractGastric cancer is the fifth most common malignancy but the third leading cause of cancer-associated mortality worldwide. Therapy for gastric cancer remain largely suboptimal making the identification of novel therapeutic targets an urgent medical need. In the present study we have carried out a high-throughput sequencing of transcriptome expression in patients with gastric cancers. Twenty-four patients, among a series of 53, who underwent an attempt of curative surgery for gastric cancers in a single center, were enrolled. Patients were sub-grouped according to their histopathology into diffuse and intestinal types, and the transcriptome of the two subgroups assessed by RNAseq analysis and compared to the normal gastric mucosa. The results of this investigation demonstrated that the two histopathology phenotypes express two different patterns of gene expression. A total of 2064 transcripts were differentially expressed between neoplastic and non neoplastic tissues: 772 were specific for the intestinal type and 407 for the diffuse type. Only 885 transcripts were simultaneously differentially expressed by both tumors. The per pathway analysis demonstrated an enrichment of extracellular matrix and immune dysfunction in the intestinal type including CXCR2, CXCR1, FPR2, CARD14, EFNA2, AQ9, TRIP13, KLK11 and GHRL. At the univariate analysis reduced levels AQP9 was found to be a negative predictor of 4 years survival. In the diffuse type low levels CXCR2 and high levels of CARD14 mRNA were negative predictors of 4 years survival. In summary, we have identified a group of genes differentially regulated in the intestinal and diffuse histo-types of gastric cancers with AQP9, CARD14 and CXCR2 impacting on patients prognosis, although CXCR2 is the only factor independently impacting overall survival.Simple summaryGastric cancer is the fifth most common malignancy and the third leading cause of cancer-associated mortality worldwide. Although several new pharmacological approaches are currently developed, surgery remains the unique valid option of treatment but survival remains very poor over the last decades. Therefore, understanding the underlying molecular mechanisms of the gastric carcinogenesis and identifying sensitive biomarkers could be helpful for the prevention and treatment of the disease. Currently, the high-throughput sequencing techniques, in particular the transcriptomic analysis (RNA-seq) represents a validated technique to obtain a molecular characterization of human cancers. Moreover, it has been established that genetic susceptibility and environmental factors, such as microbial infections may contribute to carcinogenesis. We have characterized the different patterns of gene expression, using RNA-seq analysis and correlated these findings with gastric cancer histological subtypes.


2017 ◽  
Vol 6 (2) ◽  
pp. 1462
Author(s):  
M. Priyadharshini ◽  
R. Narmadha ◽  
S. Dhanalakshmi ◽  
Rajesh Natarajan ◽  
S. Subitha ◽  
...  

<p><strong>Background:</strong> Gastric carcinomas have various pathological features. Based on patterns of growth and invasiveness, however, they fall into two types: diffuse type and intestinal type. These two types of carcinoma appear to be different in their histogenetic origins.</p><p><strong>Objectives:</strong> To analyse various types of gastric cancer reported in last five years. To compare the features of intestinal and diffuse type gastric carcinoma including gross appearance, staging, grading of tumor.</p><p><strong>Materials and Methods:</strong> This was a retrospective study of 324 gastric cancer which were surgically resected and received over 5 years. The tumors were divided into groups according to their gross and microscopic patterns. Gross appearance was classified based on Borrmann classification. Microscopic features evaluated include tumor cell type, extent of invasion, degree of maturation, formation of glandular structures, nodal metastasis.</p><p><strong>Results:</strong> Totally 320 cases of gastric cancer were received of which 218(68%) were male, 102(32%) were female. Gastric cancers are rare below the age of 30 years. Comparing the type of gastric cancer intestinal type were 269(84%), diffuse type were 24(7.5%) and other type of gastric cancer including GIST, lymphoma, mucinous adenocarcinoma were 27(8.5%). Younger patients have higher stage of lymph node metastasis in diffuse type, but not for the intestinal type.</p><p><strong>Conclusion:</strong> Gastric cancer more common in male (M:F= 2:1) and most frequently seen in 5th decade. Intestinal type constitutes the most common type of gastric tumor. Gross appearance of diffuse type was predominantly infiltrative (79%).</p>


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14670-e14670
Author(s):  
Metin Ozkan ◽  
Esra Ermis Turak ◽  
Halit Karaca ◽  
Mevlude Inanc ◽  
Veli Berk ◽  
...  

e14670 Background: HER-2 and Topo-2A genes are settled on a chromosome 17 and their co-amplification rates are high. In this study, early gastric cancer patients who received adjuvant chemo-radiotherapy and chemotherapy were evaluated with HER-2 and Topo-2A expression in association with clinical and histopathologic findings. Methods: A total of 103 gastric cancer patients were included the study. The HER-2 and Topo-2A levels were measured by immunohistochemistry in postoperative tumor materials. A standard evaluation method was admitted for HER-2 positivity, while Topo-2A nuclear staining 3+ and 4+ were considered as overexpression. Those with level 2+ or 3+ of HER-2, the FISH test were attempted. Results: The median follow-up was 19 months (ranges 2–70 months). Forty-six patients (44%) relapsed during follow-up whereas 60 patients (58%) had died. The median overall survival (mOS) was 23 months. Histopathologies of HER-2 positive patients were intestinal type in 7 (87.5%) and diffuse type in one (12.5%) patient. In the follow-up period 4 patients (50%) were died (mOS was 17 months in this group). Median overall survival was 23 months in HER-2 negative group (p=0.6). Histopathologies of Topo-2A positive patients were intestinal type in 9 (64.2%) and diffuse type in 5 (35.8%) patient. In the follow-up period 8 patients (57%) were died (mOS was 22 months in this group). Median overall survival was 23 months in Topo-2A negative group (p=0.8). Three patients (37.5%) who had HER-2 positive histopathologies also had Topo-2A positivity. Conclusions: Overexpression rates of HER-2 in gastric cancer were reported 6.8-34%. Racial differences and different scoring techniques thought to be impact the results. Co-amplification rate of HER-2 and Topo-2A was reported 34% in gastric cancer. In our study HER-2 and Topo-2A overexpression rates were 7.7% and 13.6% respectively and co-amplification of HER-2 with Topo-2A rate was 37.5% is also similar to the other studies. Stages of patients with HER-2 and Topo-2A overexpression were similar to the distribution of the overall patients. While intestinal subtypes showed a higher rate of HER-2 overexpression, the median survival times tend to be shorter in HER-2 positive patients.


2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 3-3
Author(s):  
Hark K. Kim ◽  
Jun Won Park ◽  
Jeffrey E. Green

3 Background: By creating mice deficient in E-cadherin, Smad4, and p53, we evaluated whether and how Cdh1 heterozygosity may accelerate the development and progression of gastric cancer, in combination with loss of Smad4 and p53. Methods: Compound conditional knockout mice of Smad4, p53, and E-cadherin were mated with Pdx-1-Cre transgenic mice. Offsprings were monitored for the development of gastric adenocarcinomas. Results: Gastric adenocarcinomas spontaneously arose in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice and recapitulated human diffuse type gastric cancers in histopathology. Gastric adenocarcinoma was more frequent in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice than in Pdx-1-Cre;Smad4F/F;Trp53F/F mice. When compared to Pdx-1-Cre;Trp53F/F;Cdh1F/F mice, Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice developed gastric adenocarcinomas more rapidly, suggesting that Smad4 and E-cadherin cooperate to constrain the development of gastric adenocarcinomas. Lung metastases were identified in three Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice, but not in the other genotypes. The epithelial-to-mesenchymal transition (EMT), characterized by increased vimentin expression, was identified at the invasive tumor front of gastric adenocarcinomas arising in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. This phenotype was less prominent in mice with intact E-cadherin or Smad4, indicating that the suppression of EMT by E-cadherin or Smad4 may reduce metastatic signaling pathways in Pdx-1-Cre;Smad4F/F;Trp53F/F;Cdh1F/+ mice. Conclusions: Loss of E-cadherin and Smad4 cooperate with p53 loss to promote the development and metastatic progression of gastric adenocarcinomas, with similarities to human diffuse type gastric cancer. Thus, our novel genetically-engineered mouse models reveal the importance of EMT in the metastatic progression of gastric cancers, providing a unique model to test agents targeting the metastatic progression in gastric cancers.


2017 ◽  
Vol 15 (1) ◽  
Author(s):  
Mikito Inokuchi ◽  
Hideaki Murase ◽  
Sho Otsuki ◽  
Tatsuyuki Kawano ◽  
Kazuyuki Kojima

2021 ◽  
Vol 10 (2) ◽  
pp. 13-20
Author(s):  
I.V. Vasilenko ◽  
◽  
R.B. Kondratyk ◽  
I.S. Grekov ◽  
A.M. Yarkov ◽  
...  

Introduction. The rapid development of basic science enabled us to significantly expand our understanding of various intercellular interactions. Epithelial-mesenchymal transition (EMT) is known to play a key role in certain tissue formation in the embryonic period. However, recent data show that EMT can also be observed in some pathological conditions, in particular, in various neoplasm development. This suggests that there are a number of alternative and fundamentally new mechanisms for the tumor formation and progression. Thus, EMT, which occurs in carcinomas, increases the invasiveness, immunoresistance, immunity to therapy, and the metastatic potential. Knowledge of EMT features and their timely recognition in morphological tumor diagnosis is of great predictive importance for patients. The aim of the research was to study the morphologi-cal features of epithelial-mesenchymal transition in the main types of gastric cancer. Materials and methods. We studied specimens of gastric carcinomas (N=64) including 31 cases of diffuse type, 19 cases of intestinal type, and 14 cases of mixed type. Results. All cases of the diffuse carcinoma group showed spread EMT features, which appeared already in the mucosa and completed with positive vimentin expression in 93.5% of cases. The malignant cell prolifera-tive activity was low; however, in 29% of cases we detected areas of moderate or even high activity. In the intestinal type gastric cancer, EMT developed as a result of tumor progression, it arose more often in the deeper layers and was incomplete and focal. As a rule, the proliferative activity of tumor cells was high and moderate. Vascular invasion occurred more often in diffuse type (90.3%), less often in mixed type (71.4%), and even less often in the intestine type (55.8%) gastric carcinoma. Conclusion. The variety of morphological features of EMT, its frequency, prevalence, completeness, and sequence in the development of various types of gastric cancer determines the features of their clinical manifestation and influences their further management. Keywords: gastric cancer, diagnosis, histological main types, EMT, morphopathology


2022 ◽  
Vol 27 ◽  
Author(s):  
Zhiheng Li ◽  
Zhenhua Zhao ◽  
Chuchu Wang ◽  
Dandan Wang ◽  
Haijia Mao ◽  
...  

Objective: To investigate the correlations between dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion histogram parameters and vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions in advanced gastric cancer (AGC).Methods: This retrospective study included 80 pathologically confirmed patients with AGC who underwent DCE-MRI before surgery from February 2017 to May 2021. The DCE-MRI perfusion histogram parameters were calculated by Omni Kinetics software in four quantitative parameter maps. Immunohistochemical methods were used to detect VEGF and EGFR expressions and calculate the immunohistochemical score.Results: VEGF expression was relatively lower in patients with intestinal-type AGC than those with diffuse-type AGC (p &lt; 0.05). For VEGF, Receiver operating characteristics (ROC) curve analysis revealed that Quantile 90 of Ktrans, Meanvalue of Kep and Quantile 50 of Ve provided the perfect combination of sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for distinguishing high and low VEGF expression, For EGFR, Skewness of Ktrans, Energy of Kep and Entropy of Vp provided the perfect combination of sensitivity, specificity, PPV and NPV for distinguishing high and low EGFR expression. Ktrans (Quantile 90, Entropy) showed the strongest correlation with VEGF and EGFR in patients with intestinal-type AGC (r = 0.854 and r = 0.627, respectively); Ktrans (Mean value, Entropy) had the strongest correlation with VEGF and EGFR in patients with diffuse-type AGC (r = 0.635 and 0.656, respectively).Conclusion: DCE-MRI perfusion histogram parameters can serve as imaging biomarkers to reflect VEGF and EGFR expressions and estimate their difference in different Lauren classifications of AGC.


2021 ◽  
Vol 11 ◽  
Author(s):  
Shih-Min Pai ◽  
Kuo-Hung Huang ◽  
Ming-Huang Chen ◽  
Wen-Liang Fang ◽  
Yee Chao ◽  
...  

BackgroundTo date, few reports have investigated genetic alterations and clinicopathological features in cardia and noncardia gastric cancer (GC).MethodsIn total, 435 GC patients receiving curative surgery were included. The clinicopathological features, recurrence patterns, prognoses and genetic alterations were compared between cardia and noncardia GC patients.ResultsAmong the 435 enrolled patients, 47 (10.8%) had cardia GC. Compared with noncardia GC, cardia GC was associated with more intestinal-type tumors and similar initial recurrence patterns and 5-year overall survival (OS; 50.8% vs. 50.5%, P = 0.480) and disease-free survival (DFS; 48.6% vs. 48.9%, P = 0.392) rates. For both intestinal-type GC and diffuse-type GC, the clinicopathological features and 5-year OS and DFS rates were not significantly different between the cardia and noncardia GC patients. Multivariable analysis showed that cardia GC was not an independent prognostic factor. Compared with noncardia GC, cardia GC was associated with increased PIK3CA amplification than in patients with intestinal-type GC and was associated with increased HER2 expression in patients with diffuse-type GC.ConclusionsCardia GC is not an independent prognostic factor. In cardia GC patients with intestinal-type GC, PIK3CA amplification was more common, and in those with diffuse-type GC, HER2 expression was more common. Targeted therapy may be beneficial for these patient subgroups.


2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 61-61
Author(s):  
M. Azuma ◽  
K. Ishido ◽  
A. Takeuchi ◽  
A. Naruke ◽  
K. Higuchi ◽  
...  

61 Background: We reported TS expression is an independent prognostic factor in patients with gastric cancer who received postoperative adjuvant chemotherapy with S-1 at 2010 ASCO GI (abstract 32). These pharmacogenomic finding will help for choosing chemotherapeutic agents for personalized therapy in the future. Our aim was to indicate association of TS expression with clinicopathological characteristics in the same patient population. Methods: 39 patients with stage II or III advanced gastric cancer who underwent gastrectomy were analyzed. These patients received adjuvant chemotherapy with S-1 after surgery. Formalin-fixed, paraffin-embedded tumor tissues were dissected by the laser-captured microdissection technique and analyzed for target gene expressions using a quantitative real-time PCR. Results: There were no significant differences between stage II and III in TS gene expressions. TS expression (low ≤ 0.72, high > 0.72) and histological type (intestinal and diffuse) are evaluated for PFS and OS. Patients were classified as Group I (n = 5); low TS and intestinal type, Group II (n = 14); low TS and diffuse type, Group III (n = 13); high TS and diffuse type and Group IV (n = 7); high TS and intestinal type. There were significant differences between these four groups (Kaplan-Meier survival analysis, log-rank test, PFS: p = 0.0112 OS: p = 0.0128). The survival curve showed longer survival both PFS and OS in Groups 1 > 2 > 3 > 4. In low TS situation (responders as Group I and II), there is a trend in patients with intestinal type had a longer survival compared to diffuse type (Group I > II). In high TS situation (non-responders as Group III and IV), the result are opposite, there is a trend in patients with diffuse type had a longer survival compared to Intestinal type (Group III > IV). Conclusions: These data suggest that TS gene expression levels may be molecular markers of prognostic factor for patients with adjuvant chemotherapy for resectable gastric cancer. S-1 might be effect different behavior by both histological type and TS expression. Prospective studies are needed to validate these preliminary findings. No significant financial relationships to disclose.


2021 ◽  
pp. 1-8
Author(s):  
Masakazu Yashiro ◽  
Tsuyoshi Hasegawa ◽  
Yurie Yamamoto ◽  
Gen Tsujio ◽  
Sadaaki Nishimura ◽  
...  

<b><i>Background:</i></b> Asporin (ASPN), a member of the proteoglycan family, has been shown to have a close correlation with cancer progression. It is not known whether ASPN is an oncogenic driver or a tumor suppressor in human gastric cancer. We sought herein to determine the relationship between ASPN expression and clinicopathological features of gastric cancer. <b><i>Patients and Methods:</i></b> A total of 296 gastric cancer patients (diffuse type, <i>n</i> = 144; intestinal type, <i>n</i> = 152) were enrolled. The ASPN expression level in each case was analyzed by immunohistochemistry. <b><i>Results:</i></b> ASPN was mainly found on stromal cells, especially on fibroblasts in tumor stroma, i.e., cancer-associated fibroblasts. The ASPN expression on either cancer cells or stromal cells was significantly high in macroscopic scirrhous-type tumors (<i>p</i> &#x3c; 0.001) and histologically abundant stroma-type tumors (<i>p</i> &#x3c; 0.001). Interestingly, a Kaplan-Meier survival curve of the 144 cases of diffuse-type gastric cancer revealed a significantly poorer prognosis in patients with ASPN-positive expression (<i>p</i> = 0.043; log rank) compared to those with ASPN-negative expression, but the prognoses were not significantly different in these subgroups of the 152 cases of intestinal-type gastric cancer. A multivariate analysis with respect to overall survival showed that ASPN expression on stromal cells and/or cancer cells was significantly correlated with overall survival in patients with diffuse-type gastric cancer (<i>p</i> = 0.041). <b><i>Conclusion:</i></b> In gastric cancer, ASPN was expressed mainly on stromal cells and partially on cancer cells. ASPN expression on stromal cells and/or cancer cells might be a useful prognostic marker in patients with diffuse-type gastric cancer.


Sign in / Sign up

Export Citation Format

Share Document