Clinicopathological Features Of Gastric Cancer Research Articles

Role of P2X7 receptor in the progression and clinicopathological characteristics of gastric cancer

P2X7 receptor (P2X7R) plays a role in regulating tumor progression, but it is unclear whether P2X7R affects the pathological characteristics of patients with gastric cancer and the activity of gastric cancer cells. Therefore, this study preliminarily investigated the relationship between P2X7R and clinicopathological features of patients with gastric cancer, and further explored the effect of P2X7R on the proliferation, migration and invasion of gastric cancer cells through functional experiments. The results showed that P2X7R was highly expressed in gastric cancer tissues and gastric cancer cells. High expression of P2X7R was closely related to lymphatic metastasis, vascular invasion and Tumor-Node-Metastasis (TNM) stage in patients with gastric cancer. High expression of P2X7R predicted poor overall survival in patients. Moreover, the activation of P2X7R by ATP and its analogue BzATP increased the calcium current of gastric cancer cells, enhanced YF actin stress and cell viability, and promoted the proliferation, migration and invasion of gastric cancer cells. While P2X7R antagonists (A438079 and AZD9056) inhibited the proliferation, migration and invasion of gastric cancer cells induced by ATP. Therefore, the data obtained in this experiment suggest that P2X7R may be another potential molecular target for the prevention and treatment of gastric cancer.

NTRK gene alterations were enriched in hepatoid or enteroblastic differentiation type of gastric cancer

AimsCurrently, the clinicopathological characteristics of gastric cancer (GC) with oncogenic NTRK alterations are not well known. Although NTRK fusion has been identified as prevalent in DNA mismatch repair protein deficient...

Landscape of homologous recombination deficiency in gastric cancer and clinical implications for first-line chemotherapy.

Homologous recombination deficiency (HRD) is one of the crucial hallmarks of cancer. It is associated with a favorable response to platinum-based chemotherapy. We explored the distinctive clinicopathological features of gastric cancer (GC) with HRD and the clinical significance of HRD in platinum-based first-line chemotherapy for unresectable metastatic GC. We enrolled 160 patients with GC in this study. Their tumor samples were subjected to genomic profiling utilizing targeted tumor sequencing. HRD was defined as the presence of alterations in any of 16 HR genes (BARD1, BLM, BRCA1, BRCA2, BRIP1, MRE11A, NBN, PALB2, PARP1, POLD1, RAD50, RAD51, RAD51C, RAD51D, WRN, and XRCC2). The clinicopathological features and treatment outcomes of first-line chemotherapy for unresectable metastatic GC were compared between HRD and non-HRD groups. Forty-seven patients (29.4%) were classified into the HRD group. This group had a significantly lower proportion of macroscopic type 3 or 4 tumors and higher TMB than the non-HRD group. Among patients who underwent platinum-based first-line chemotherapy, the HRD group had a greater response rate and longer progression-free survival after treatment (median 8.0months vs. 3.0months, P = 0.010), with an adjusted hazard ratio of 0.337 (95% confidence interval 0.151-0.753). HRD status was not associated with treatment outcomes in patients who did not undergo platinum-based chemotherapy. Low proportion of macroscopic type 3 or 4 tumors and a high TMB are distinctive features of GC with HRD. HRD status is a potential predictive marker in platinum-based first-line chemotherapy for unresectable metastatic GC.

Expression of CD151 in Gastric Cancer Tissues and Its Clinical Significance

Objective: To explore the expression of CD151 in gastric cancer tissues and its clinical significance. Methods: Immunohistochemistry was employed to detect the expression of CD151 in gastric cancer tissues and adjacent normal tissues.The relationship between CD151 expression and the clinicopathological characteristics of gastric cancer was analyzed. Results: The expression of CD151 in gastric cancer tissues was significantly higher than in adjacent normal tissues (P <0.05). It was associated with the degree of differentiation, depth of invasion, lymph node metastasis, and TNM staging ofgastric cancer. The survival time of patients with high CD151 expression was significantly shorter than that of those withlow expression (P < 0.05). Conclusion: High expression of CD151 in gastric cancer tissues is correlated with the malignantbiological behavior of gastric cancer and can serve as an indicator for evaluating the prognosis of gastric cancer.

Characteristics of Early Gastric Cancer in a Patient with a History of Helicobacter pylori Infection and No History of Eradication Therapy

Objective The characteristics of gastric cancer in patients with atrophic mucosa and no apparent history of Helicobacter pylori eradication have not been thoroughly investigated. Therefore, this study examined the clinicopathological characteristics of gastric cancer in these patients. Methods We retrospectively examined the endoscopic and pathological characteristics of gastric cancer in patients who underwent endoscopic submucosal dissection. Patients We divided the patients into 2 groups: those with gastric atrophy and no history of eradication (group A; n=102) and those with a history of eradication (group B; n=161). In group A, patients were further divided into mild atrophy (group C) and severe atrophy (group D) groups, while group B was further divided into those who underwent eradication treatment >5 years ago (group E) and those who underwent eradication 1-5 years ago (group F). Results Group A comprised significantly older individuals (75±8.0 vs. 71±7.5 years old, p<0.001) with a higher frequency of elevated gastric cancer than group B (32.4% vs. 17.4%, p=0.006). Compared with group E, group A was older and had a greater incidence of elevated gastric cancer. The incidence of gastric cancer in the U or M region was lower in group C than in group D. Conclusion Gastric cancer in patients with gastric atrophy and no history of eradication was associated with an older age and higher frequency of elevated-type morphology than in those with a history of eradication.

Prognostic and clinicopathological significance of mucin family members expression in gastric cancer: a meta-analysis.

Mucin family members have been reported to be widely expressed in gastric carcinoma with diverse functions. Several important mucins exert the function of tumorigenesis or progression in gastric cancer (GC). Here, we conduct this meta-analysis to evaluate the association between mucin expression and clinicopathological features in GC. Literature searches were performed in PubMed, Embase, The Cochrane Library, and ISI Web of Science, and, finally, 28 studies met our criteria. Odds ratios or hazard ratios with 95% confidence intervals were calculated to evaluate the effect quantity. We analyzed the expression of MUC1, MUC2, MUC5AC, and MUC6 and their clinicopathological characteristics separately at the same time. Twenty-eight studies that contain 4,603 patients were included in our meta-analysis. MUC1 was associated with gender, Lauren classification, depth of tumor invasion, TNM, vascular invasion, lymph metastasis, and lymphatic invasion, WHO grade, as well as the 5-year survival rate. MUC2 was significantly correlated with lymphatic invasion and WHO grade. MUC5AC was highly positive in gender, depth of tumor invasion, WHO grade, TNM, lymph metastasis, and lymphatic invasion. Moreover, cases with decreased MUC5AC expression were correlated with less 5-year survival. MUC6 was only related with lymphatic invasion. Our meta-analysis showed that MUC1 and MUC5AC had prognostic value in GC detected by immunohistochemistry. MUC1 and MUC5AC were also associated with some other significant clinicopathological parameters. Moreover, MUC2 and MUC6 also exert their influence in lymphatic invasion. However, further enlarged study awaits to verify our conclusion to deeply explore the role of mucin family members in GC.

Gastric Cancer in the Lesser and Greater Curvature: A Comparative Analysis from a Single Western Center.

To date, the different clinicopathological characteristics of gastric cancer (GC) in the lesser curvature and greater curvature remain unclear. The aim of this study was to investigate the different features of the tumors in the two sites and provide new strategy for a tailored therapy. Between January 2003 and December 2019, 121 patients with GC located in the lesser or greater curvature were surgically treated with curative intent. Data about clinico-pathological features were retrospectively analyzed. In addition, we analyzed the different lymph node patterns according to the lymph node (LN) metastasis between the two groups of patients. No statistically significant differences were found regarding the 5-year overall survival (5y-OS) and 5y disease-free survival (5y-DFS) between patients with GC in the two sites (p=0.94 and p=0.98, respectively). Considering TNM pathological stage, patients with GC in the lesser curvature in stage II and III, showed a worse survival than those with GC in the greater curvature (stage II 5y-OS: 80 vs. 100% and stage III 5y-OS: 18.9 vs. 55.5%). Considering the median value of metastasis LNs, GC in the greater curvature metastasized more often to LN stations no. 8, 10, and 11, whereas GC in the lesser curvature to LN stations no. 8, 9, and 12. GC in the lesser curvature showed a worse prognosis than GC in the greater curvature. Therefore, GC in the lesser curvature could undergo a more aggressive surgery, including an extended lymphadenectomy, and a close follow-up.

Clinico-pathological evaluation of gastric adeno carcinoma with reference to ki-67 LI immuno-staining

Gastric cancer is a life-threatening disease accounting for the one of the most common types of disease and second most that cause the cancer which lead to death. Many molecular markers were established as a possible prognostic factor apart from routine grading and TNM staging. The variable prognosis of gastric cancer within a pathological grade necessitates a newer marker which can be correlated with the prognosis and aggressiveness of the disease. ki-67 is a nuclear protein that is known as a marker of cellular proliferation and ribosomal RNA transcription. According to analysis, the ki-67 is a nuclear proliferation antigen affecting the health of the people as it cannot be cycle in the resting phase. Moreover, the fraction of ki-67 is clinical course of various cancers. To evaluate the expression of ki-67 LI in gastric cancer and correlate the findings with various clinico-pathological features.Prospective study was conducted from October 2018 to September 2021 at the department of Pathology, MKCG Medical College, Berhampur, Odisha. Two sets of 3–4-micron thickness of tissue sections prepared from blocks of histologically confirmed cases of gastric adenocarcinoma were taken, one for routine H&amp;E and other for ki-67 LI IHC study. IHC protocol of DAKO was followed along with DAB visualisation. The results were correlated with different clinico-pathological features of Gastric cancer. Higher ki-67 LI was correlated significantly with tumour location, histological grade and type but not with age and sex.In our study, IHC assessment of ki-67 LI correlates well with histological grade and type of tumour. ki-67 LI can be taken as a useful method in identifying aggressiveness of the tumour with an indication of adjuvant chemotherapy. Post-operative follow-up and large sample size could throw more light.

Prediction and therapeutic targeting of the tumor microenvironment-associated gene CTSK in gastric cancer

BackgroundCathepsin-K (CTSK) is overexpressed in Gastric cancer (GC) and the mechanism of its overexpression in GC is still unclear. The present work found CTSK as a potential predictive biomarker and immunotherapeutic target for GC based on the tumor microenvironment (TME).MethodsFrom public databases, gene expression profiles and clinical data of GC were downloaded to analyze the distribution of stromal and immune cells and tumor abundance in TME. Differentially expressed genes (DEGs) associated with TME were obtained by differential analysis, followed by cross-screening to obtain CTSK as a gene associated with TME. Next, a series of methods and tools were employed to explore the relationships between clinicopathological features of GC and CTSK expression as well as prognosis, tumor immune microenvironment, immune checkpoints and drug sensitivity. And GSEA was used to investigate the potential role of CTSK in the tumor microenvironment of GC.ResultsFrom the dataset, we obtained a total of 656 DEGs associated with TME and the stromal component of TME was found to be closely involved in GC prognosis. CTSK was cross-screened as the key gene associated with TME by the PPI network and univariate Cox regression analysis. Pan-cancer analysis revealed significant high expression of CTSK in a variety of cancers. Subsequently, we hypothesized that high-expressed CTSK was closely correlated with poor prognosis and lymph node metastasis of tumors, and that CTSK, a GC TME-related gene, was largely involved in a range of biological behaviors of tumors, with a significant correlation between several immune cells.ConclusionCTSK was validated as a potential prognostic biomarker related to TME of GC and could be a promising next-generation immunotherapeutic target for GC.

Helicobacter pylori infection associated DNA methylation in primary gastric cancer significantly correlates with specific molecular and clinicopathological features.

Helicobacter pyloriinduces DNA methylation in gastric mucosa, which links to gastric cancer (GC) risk. In contrast, CpG island methylator phenotype (CIMP) is defined as high levels of cancer-specific methylation and provides distinct molecular and clinicopathological features of GC. The association between those two types of methylation in GC remains unclear. We examined DNA methylation of well-validated H. pylori infection associated genes in GC and its adjacent mucosa and investigated its association with CIMP, various molecular subtypes and clinical features.We studied 50 candidate loci in 24 gastric samples to identify H. pylori infection associated genes. Identified loci were further examined in 624 gastric tissue from 217 primary GC, 217 adjacent mucosa, and 190 mucosae from cancer-free subjects.We identified fivegenes (IGF2, SLC16A2, SOX11, P2RX7, and MYOD1) as hypermethylated in H. pylori infected gastric mucosa. In non-neoplastic mucosa, methylation of H. pylori infection associated genes was higher in patients with GC than those without. In primary GC tissues, higher methylation of H. pylori infection associated genes correlated with CIMP-positive and its related features, such as MLH1 methylated cases. On the other hand, GC with lower methylation of these genes presented aggressive clinicopathological features including undifferentiated histopathology, advanced stage at diagnosis.H. pylori infection associated DNA methylation is correlated with CIMP, specific molecular and clinicopathological features in GC, supporting its utility as promising biomarker in this tumor type.

No significant association between non-Helicobacter pylori Helicobacter infection with gastritis-related indices and gastric cancer

Non-Helicobacter pylori Helicobacter (NHPH) has recently been linked to various gastric diseases. However, the relationship between NHPH infection and gastric cancer remains controversial. This study aimed to identify the effect of NHPH infection on gastritis and gastric cancer development. Formalin-fixed paraffin-embedded tissues were obtained from 73 patients with gastric cancer, of whom 21 cases were Helicobacter pylori (Hp) current infection, 37 cases were Hp previous infection, and 15 cases were Hp naïve infection, and were screened for NPHPs using a polymerase chain reaction. The results were compared with NHPH infection rates in the patients with gastritis-related diseases reported in the previous study . We evaluated the association of NHPH infection with gastritis and clinicopathological features of gastric cancer. NHPH infection rates were 4/21 (19%) in "Hp current" patients, 4/37 (11%) in "Hp previous" infection patients, and 1/15 (7%) in "Hp naïve" patients, showing no significant difference in infection rates based on Hp infection status. NHPH infection rates in gastric cancer patients were similar to those in the patients with gastritis-related diseases reported in the previous study. A comparison of NHPH-positive and negative patients showed no significant differences in atrophic gastritis status, serum gastritis markers, or clinicopathological characteristics of gastric cancer, such as localization, size, gross type, differentiation, or depth. The association between gastric cancer and NHPH infection would have important implications for gastric cancer prevention, diagnostics, and treatment, however, no significant association was found in this particular population.

TSPAN8 regulates EGFR/AKT pathway to enhance metastasis in gastric cancer.

Tetraspanin 8 (TSPAN8), a transmembrane glycoprotein, is implicated in various pathological conditions including human malignancies. However, the roles and underlying mechanisms of TSPAN8 in promoting gastric cancer(GC)progression are yet to be fully understood. Our study found that TSPAN8 expression was significantly elevated in GC tissues. We also observed a positive correlation between high TSPAN8 expression and various clinicopathological characteristics of GC, including tumor differentiation, invasion depth, lymph node metastasis, and clinical stage. Moreover, the elevated TSPAN8 expression was indicative of poor prognosis. Functionally, we observed that knockdown of TSPAN8 significantly attenuated while overexpression of TSPAN8 promoted GC cell migration and invasion. In vivo experiments, knockdown of TSPAN8 suppressed lung metastasis in nude mice. We further explored the underlying mechanisms of TSPAN8 and found that it regulated EGFR expression in GC cells by accelerating phosphorylation of EGFR and AKT. Our study reveals that TSPAN8 plays a significant role in promoting tumor metastasis by activating the EGFR/AKT pathway, indicating that it may serve as a promising therapeutic target of gastric cancer.

FMO family may serve as novel marker and potential therapeutic target for the peritoneal metastasis in gastric cancer.

To explore the relationship between flavin-containing monooxygenases (FMOs) and peritoneal metastasis (PM) in gastric cancer (GC). TIMER 2.0 was used to perform pan-cancer analysis and assess the correlation between the expression of FMOs and cancers. A dataset from The Cancer Genome Atlas (TCGA) was used to analyze the correlation between FMOs and clinicopathological features of GC. PM is well established as the most common mode of metastasis in GC. To further analyze the correlation between FMOs and PM of GC, a dataset was obtained from the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database. The results were validated by immunohistochemistry. The relationship between FMOs and PM of GC was explored, and a novel PM risk signature was constructed by least absolute shrinkage and selection operator (LASSO) regression analysis. The regression model's validity was tested by multisampling. A nomogram was established based on the model for predicting PM in GC patients. The mechanism of FMOs in GC patients presenting with PM was assessed by conducting Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses in TCGA and GEO datasets. Finally, the potential relationship between FMOs and immunotherapy was analyzed. The pan-cancer analysis in TCGA and GEO datasets showed that FMO1 was upregulated, while FMO2 and FMO4 were downregulated in GC. Moreover, FMO1 and FMO2 correlated positively with the T and N stage of GC in the TCGA dataset. FMO1 and FMO2 expression was a risk factor for GC (hazard ratio: 1.112 and 1.185). The overexpression of FMO1 was significantly correlated with worse disease-free-survival (DFS) and overall survival (OS). However, no relationship was found between FMO2 expression in GC and DFS and OS. PM was highly prevalent among GC patients and typically associated with a worse prognosis. FMO1 was highly expressed in GC with PM. FMO1 and FMO2 were positively correlated with PM in GC. We identified a 12-gene panel for predicting the PM risk signature by LASSO (Area Under Curve (AUC) = 0.948, 95%CI: 0.896-1.000). A 10-gene panel for PM prediction was identified (AUC = 0.932, 95%CI: 0.874-0.990), comprising FMO1 and FMO2. To establish a model for clinical application, a 7-gene panel was established (AUC = 0.927, 95% CI: 0.877-0.977) and successfully validated by multisampling. (AUC = 0.892, 95% CI: 0.878-0.906). GO and KEGG analyses suggest that FMO1 and FMO2 regulate the extracellular matrix and cell adhesion. FMO1 and FMO2 were positively correlated with the immune score of GC, and their expression was associated with the infiltration of immune cells. PM in GC is strongly correlated with FMOs. Overall, FMO1 and FMO2 have huge prospects for application as novel diagnostic and therapeutic targets.

The clinicopathological characteristics of gastric cancer and precancerous conditions in gastric DLBCL and MALT lymphoma patients: a multi-center retrospective study

Objective The objective of this study is to explore the clinicopathological characteristics of gastric cancer and precancerous conditions in patients with primary gastric lymphoma. Methods We analyzed 474 cases of primary gastric lymphoma, mainly DLBCL and MALT, from three clinical centres retrospectively, and compared the clinicopathological parameters of primary gastric lymphoma patients complicated with gastric cancer, precancerous conditions, or with no complications. Results A total of 5.1% of the patients with primary gastric lymphoma were diagnosed with gastric cancer, including metachronous gastric adenocarcinoma (3.2%) and synchronous gastric adenocarcinoma (1.9%). Of the patients with gastric lymphoma, 14.6% had precancerous conditions including atrophy (14.6%), intestinal metaplasia (8.9%), and low-grade intraepithelial neoplasia (1.9%). Primary gastric lymphoma patients with an ulcerative type (p = 0.009) and Lugano classification stage IIE + IV (p < 0.001) lymphoma had a higher risk of complicating with gastric cancers or precancerous conditions. The rate of infection of Helicobacter pylori (Hp) was 68.4% in patients with primary gastric lymphoma, which was higher in patients with MALT lymphoma (p < 0.001), Lugano classification stage I + II (p < 0.001), and patients complicated with precancerous conditions and gastric cancer (p < 0.001), especially gastric cancer of the intestinal type (p = 0.04). Gastric cancer (95.8%) and precancerous conditions (91.3%) occurred mostly in Hp-infected primary gastric lymphoma patients, with a minor subset of Hp-eradicated patients. Primary gastric lymphoma patients had a higher detection rate of early gastric cancer (25.0%) and a five-year survival rate (40.0%) than the general Chinese population. Conclusions Patients with primary gastric lymphoma have a high risk of developing gastric cancer and precancerous conditions, and this risk may be related to Helicobacter pylori infection. Follow-up of primary gastric lymphoma provides an opportunity for the detection of early gastric cancer. Key messages 5.1% of the patients with primary gastric lymphoma were diagnosed with gastric cancer. 14.6% of the patients with gastric lymphoma had premalignant lesions including atrophy (14.6%), intestinal metaplasia (8.9%), and low-grade intraepithelial neoplasia (1.9%). Primary gastric lymphoma patients complicating with gastric cancer had a higher infection rate of Helicobacter pylori (100.0%), a detection rate of early gastric cancer (25.0%) and a five-year survival rate (40.0%) than the general Chinese population.

The LINC00501-HSP90B1-STAT3 positive feedback loop promotes malignant behavior in gastric cancer cells

Long non-coding RNAs (lncRNAs) have been implicated in gastric cancer (GC) carcinogenesis and progression. However, the role of linc00501 in GC growth and metastasis remains unclear. In this study, we found that linc00501 was frequently upregulated in GC cells and tissues and was closely related to adverse GC clinicopathological features. Aberrant overexpression of linc00501 promoted GC cell proliferation, invasion, and metastasis both in vitro and in vivo. Mechanistically, linc00501 stabilized client protein STAT3 from deubiquitylation by directly interacting with cancer chaperone protein HSP90B1. Furthermore, the linc00501-STAT3 axis modulated GC cell proliferation and metastasis. In turn, STAT3 bound directly to the linc00501 promoter and positively activated linc00501 expression, thus forming a positive feedback loop, thereby accelerating tumor growth, invasiveness, and metastasis. In addition, linc00501 expression was positively correlated with STAT3 and p-STAT3 protein expression levels in gastric clinical samples. Our results reveal that linc00501 acts as an oncogenic lncRNA and that the linc00501-HSP90B1-STAT3 positive feedback loop contributes to GC development and progression, suggesting that linc00501 may be a novel potential biomarker and treatment target for GC.

PD‐L1 expression by different scoring methods and different cutoff values and correlation with clinicopathological characteristics in gastric cancer: A retrospective study

AbstractWe retrospectively enrolled 325 gastric cancer (GC) patients to investigate the associations of programmed death ligand‐1 (PD‐L1) expression with clinicopathological characteristics by different scoring methods and different cutoff values. PD‐L1 expression was evaluated by the tumor proportion score (TPS) and the combined positive score (CPS). The positive rate of PD‐L1 TPS ≥1%, CPS ≥1, CPS ≥5 and CPS ≥10 in our study were 12.0%, 87.4%, 69.8% and 42.2%, respectively. Multivariate analysis showed that PD‐L1 CPS ≥5 was related to high expression of Ki67 (OR = 2.658, 95% CI: 1.401–5.045, p = .003) and pTNM staging (p = .033). PD‐L1 CPS ≥10 was correlated with larger tumor size (OR = 2.322, 95% CI: 1.052–5.127, p = .037) and lymph node metastasis (OR = 2.495, 95% CI: 1.293–4.814, p = .006). It is expected that these results can provide a reference for screening GC patients with high PD‐L1 expression level.

Association of genomic instability of CDH1 gene with clinicopathological characteristics of gastric cancer

To assess the association of genomic instability of epithelial cadherin 1 (CDH1) gene and clinicopathological characteristics of gastric cancer. In total 120 paraffin-embedded gastric cancer tissue specimen were prepared, and genomic DNA was extracted. The genomic instability of the CDH1 gene was analyzed by immunohistochemistry and silver staining PCR-single-strand conformation polymorphism. The number of information individuals (heterozygotes) was 98 for the D16S752 locus. The detection rates for microsatellite instability (MSI) and loss of heterozygosity (LOH) at the D16S752 locus and the positive rate of CDH1 protein were 19.39%, 16.33% and 51.02%, respectively. The detection rate of MSI in TNM stages I or II was significantly higher than that in stages III or IV (P<0.05) while the detection rate of LOH was significantly lower than that in stages III or IV (P<0.05). The positive rate of CDH1 protein in TNM stages III or IV was significantly lower than that in stages I or II (P<0.05). The detection rate of MSI of cases with lymph node metastasis was significantly lower than that of without lymph node metastasis (P<0.05) while the detection rate of LOH was significantly higher than that without lymph node metastasis (P<0.05). The positive rate of CDH1 protein in patients with lymph node metastasis was significantly lower than that in patients without lymph node metastasis (P<0.05). The positive rate of CDH1 protein in MSI-positive group was significantly higher than that in MSI-negative group (P<0.05), and the positive rate of CDH1 protein in the LOH-positive group was significantly lower than that the LOH-negative group (P<0.05). The genomic instability of the CDH1 gene is associated with the progression of gastric cancer. MSI at the D16S752 locus may be used as a molecular marker for early gastric cancer, while LOH at this locus mostly occurs in advanced gastric cancer and can be regarded as an effective indicators for malignancy evaluation and prognosis.

Gastric cancer with Epstein-Barr virus heterogeneity: Evaluation of the frequency, clinicopathologic features, and genomic profiles.

Epstein-Barr virus (EBV)-associated gastric carcinoma accounts for approximately 10% of gastric carcinomas worldwide and is characterized by distinct clinicopathological features. Recently, the use of EBV as a reliable biomarker for immunotherapy of gastric cancer has been gaining focus. We aimed to investigate the frequency and clinicopathological characteristics of gastric cancer with EBV heterogeneity. EBV status was evaluated using EBV-encoded RNA in situ hybridization in 3499 consecutive surgical cases of gastric cancer. We selected heterogeneous EBV cases and evaluated their clinicopathological features. CD8, programmed death-ligand 1 status, and genomic profiles were separately evaluated in each EBV-positive and EBV-negative area of heterogeneous cases. EBV positivity was identified in 214 (6.1 %) cases, of which four (1.9 %) were found to be EBV heterogeneous. Of the four heterogeneous EBV cases, three were composed of two histologically distinct patterns that correlated with EBV status. The EBV-positive area consisted of poorly differentiated adenocarcinomas with increased lymphocytic infiltration. Notably, the fraction of EBV-positive cells was more infiltrative, and metastatic tumors in the lymph nodes were all EBV-positive. The average number of CD8-positive cells was higher in EBV-positive areas than in EBV-negative areas (P=0.030). Each EBV-positive and EBV-negative area revealed some different genomic alterations, including FGFR2 amplification. In conclusion, we have reported four cases of gastric cancer with heterogeneous EBV status, which accounted for 1.9% of EBV-positive gastric cancers. Each EBV-positive and-negative area revealed a distinct histological pattern, immune microenvironment, and some different genomic profiles.

Abstract 6199: Fusion genes: Novel therapeutic targets for gastric signet ring cell carcinoma

Abstract Background: Gastric cancer (GC) is one of the most common lethal malignancies in the world. In recent years, clinicopathological characteristics of GC are changing, marked by increasing incidence of gastric signet ring cell carcinoma (GSRCC) histology. However, at present, no effective therapeutic targets for GSRCC. Fusion genes are considered as ideal therapeutic targets for various cancers with the development of sequencing technique. We attempted to target fusion genes to treat GSRCC. Methods: We used STAR-Fusion, STAR-Seqr, Arriba to get fusion genes in 417 GC samples in The Cancer Genome Atlas (TCGA). Fusion genes identified simultaneously by at least two software are considered “real” fusion genes. Next, we included 556 GC samples of our specimen bank, including 64 GSRCC in this study. All histopathologic diagnoses were reviewed by at least two senior pathologists independently. Clinical information was retrospectively collected and the overall survival (OS) was measured from the date of surgery to the date of death or the last follow-up visit. Formalin fixed paraffin-embedded (FFPE) tissue were collected for next-generation sequencing (NGS) in a 450-gene panel assay. Results: Among 417 GC samples in TCGA, we detected fusion genes in 283 (68%) samples. On average, each GC samples contained 7 fusion genes. And, a single sample contained a maximum of 85 fusion genes. We noticed that one GC sample had FGFR2-TACC2 fusion, which is recurrent and meaningful in intrahepatic cholangiocarcinoma and urothelium carcinoma. On the other hand, among 556 GC samples from our specimen bank, GSRCC patients had lower tumor mutation burden (TMB-L) (P=0.001) than non-SRCC patients. However, we detected gene fusions in 20.3% (13/64) GSRCC patients. GSRCC patients with gene fusions had a higher N stage (P=0.001) and a higher tumor stage (P=0.010) defined by 8th American Joint Committee on Cancer (AICC) criterion. Moreover, GSRCC patients harboring gene fusions (n=9) had poorer overall survival (OS) in comparison with patients without any gene fusion (n=19) (16.0 months vs 21.0 months, P=0.043). In addition, FGFR2 gene fusions (FGFR2-VTI1A and TACC2-FGFR2) were recurrently detected in 3.1% GSRCC tumor samples. We stably expressed TACC2-FGFR2 in gastric cancer cell lines. Using qRT-PCR, we found FGFR2 mRNA levels were increased in TACC2-FGFR2-expressing GC cells and IHC showed TACC2-FGFR2 upregulated FGFR2 protein expression in TACC2-FGFR2-expressing GC cells. Also, TACC2-FGFR2-expressing GC cells were more sensitive to FGFR2 inhibitors. Conclusions: Our observation revealed that fusion genes were recurrent in GSRCC and might associate to shorter OS. FGFR2 fusion genes were recurrent in GSRCC and FGFR2 inhibitors might be a new therapeutic target for GSRCC. Citation Format: Yue Wang, Tao Shi, Xuan Wang, Jinwei Hu, Lixia Yu, Qin Liu, Nandie Wu, Baorui Liu, Jia Wei. Fusion genes: Novel therapeutic targets for gastric signet ring cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6199.

Relationship between tumor infiltrating lymphocytes and clinicopathological features in Peruvian gastric cancer.

e16080 Background: Role of tumor-infiltrating lymphocytes (TIL) over clinicopathological features including Mismatch Repair (MMR), HER2 status, Epstein Barr Virus (EBV) and Helicobacter pylori (HP) infection is not well understood in gastric cancer (GC). Methods: TIL level and HP infection was also evaluated in H&amp;E from 503 Peruvian GC patients who underwent surgery. Density of CD3+ T cells, CD8+ cytotoxic T cells, CD163 M2 macrophages, as well as MMR and HER2 status were determined by immunohistochemistry. HP and EBV infection was also detected by qPCR in a 234 cases subset. Results: Median age was 62 years and 50.1% were female, most tumors were grade 3 (59.1%), intestinal subtype (44.8%) and stage III (59.8%). MMR loss was found in 29.4% and HER2+ in 4.7%. HP+ was detected by H&amp;E in 55.7% and by qPCR in 63.7%. EBV+ by qPCR was found in 20.5% and co-infection along with HP in 9.4% (22/234). Stage (p &lt; 0.001), intestinal histology (IH) (p = 0.019), grade (p = 0.006) and lymphovascular invasion (p &lt; 0.001) were associated with longer survival. Median TIL was higher in invasive border (IB) and stromal (ST) than intratumoral (IT) compartment but there were significantly correlated (p &lt; 0.001). High IT TIL was associated with absence of HP H&amp;E (p = 0.009). High ST TIL was associated with older age (p &lt; 0.001), IH (p &lt; 0.001), grade 1 (p = 0.009), lower stage (p = 002), MMR loss (p = 0.019) and EBV+ (p = 0.001). Density of CD3 and CD8 were significantly correlated in IT and ST compartments (p &lt; 0.001). High CD3 density in IT compartment was associated with grade 3 (p = 0.001) and HP- (p = 0.02), and in ST was associated with IH (p = 0.005), grade 1- 2 (p = 0.002) and MMR loss (p = 0.04). High IT CD8 was associated with HER2- (p = 0.016), HP- (p = 0.014) and EBV+ (p = 0.012). High ST CD8/CD3 ratio was associated with diffuse histology (p = 0.034), grade 3 (p = 0.013), more advanced stage (p = 0.022) and recurrence (p = 0.014). High ratio of IT CD8/CD3 was associated with MMR loss (p = 0.007). High ST TIL was associated with longer DFS (p = 0.007). Lower ratio of CD8/CD3 was associated with longer OS (p = 0.024) and DFS (p = 0.02). Conclusions: TIL levels and infiltrating immune subpopulations differs by clinicopathological features in GC including MMR loss, HER2 expression EBV and HP infection. ST CD8/CD3 was associated with recurrence and shorter DFS.