Different Subtypes Of Gastric Cancer Research Articles

Clinical Features of Gastric Signet Ring Cell Cancer: Results from a Systematic Review and Meta-Analysis.

Conflicting results about the prognostic relevance of signet ring cell histology in gastric cancer have been reported. We aimed to perform a meta-analysis focusing on the clinicopathological features and prognosis of this subgroup of cancer compared with other histologies. A systematic literature search in the PubMed database was conducted, including all publications up to 1 October 2021. A meta-analysis comparing the results of the studies was performed. A total of 2062 studies referring to gastric cancer with signet ring cell histology were identified, of which 262 studies reported on its relationship with clinical information. Of these, 74 were suitable to be included in the meta-analysis. A slightly lower risk of developing nodal metastases in signet ring cell tumours compared to other histotypes was found (especially to undifferentiated/poorly differentiated/mucinous and mixed histotypes); the lower risk was more evident in early and slightly increased in advanced gastric cancer. Survival tended to be better in early stage signet ring cell cancer compared to other histotypes; no differences were shown in advanced stages, and survival was poorer in metastatic patients. In the subgroup analysis, survival in signet ring cell cancer was slightly worse compared to non-signet ring cell cancer and differentiated/well-to-moderately differentiated adenocarcinoma. Most of the conflicting results in signet ring cell gastric cancer literature could be derived from the lack of standardisation in their classification and the comparison with the different subtypes of gastric cancer. There is a critical need to strive for a standardised classification system for gastric cancer, fostering clarity and coherence in the forthcoming research and clinical applications.

Adherence to the Mediterranean Diet and Risk of Gastric Cancer: A Systematic Review and Meta-Analysis.

Available results on the association between the Mediterranean diet (MD) and gastric cancer (GC) incidence are controversial. The present study aimed to determine the correlation between different subtypes of GC and MD adherence. This meta-analysis was registered on PROSPERO (CRD42021284432). We searched Embase, PubMed, Cochrane Library, and Web of Science from inception through 22 April 2023 to retrieve relevant studies. A random-effects model was used to pool odds ratios (ORs) with 95% confidence intervals (CIs). Eleven studies were included in the meta-analysis. Pooled analyses revealed that adherence to the MD was inversely associated with GC risk (ORcc, 0.43; 95% CI, 0.29 to 0.63; ORcoh, 0.84; 95% CI, 0.77 to 0.92). Higher MD adherence was significantly associated with a reduced GC risk in male (ORcc, 0.78; 95% CI, 0.65 to 0.93; ORcoh, 0.81; 95% CI, 0.65 to 1.01), but not in female (ORcc, 0.83; 95% CI, 0.68 to 1.01; ORcoh, 1.04; 95% CI, 0.82 to 1.31). Furthermore, adherence to the MD possibly decreased the risk of gastric cardia adenocarcinoma (GCA) (ORcc, 0.64; 95% CI, 0.49 to 0.83; ORcoh, 0.88; 95% CI, 0.76 to 1.02) and gastric non-cardia adenocarcinoma (GNCA) (ORcc, 0.68; 95% CI, 0.59 to 0.79; ORcoh, 0.85; 95% CI, 0.78 to 0.94). Our results indicate that adherence to the MD reduces the risk of GC and its subtypes.

Diagnostic Performance of Positron Emission Tomography with Fibroblast-Activating Protein Inhibitors in Gastric Cancer: A Systematic Review and Meta-Analysis.

Various papers have introduced the use of positron emission tomography (PET) with [68Ga]Ga-radiolabeled fibroblast-activation protein inhibitor (FAPi) radiopharmaceuticals in different subtypes of gastric cancer (GC). Our aim was to assess the diagnostic performance of this novel molecular imaging technique in GC with a systematic review and meta-analysis. A straightforward literature search of papers concerning the diagnostic performance of FAP-targeted PET imaging was performed. Original articles evaluating this novel molecular imaging examination in both newly diagnosed GC patients and GC patients with disease relapse were included. The systematic review included nine original studies, and eight of them were also eligible for meta-analysis. The quantitative synthesis provided pooled detection rates of 95% and 97% for the assessment of primary tumor and distant metastases, respectively, and a pooled sensitivity and specificity of 74% and 89%, respectively, for regional lymph node metastases. Significant statistical heterogeneity among the included studies was found only in the analysis of the primary tumor detection rate (I2 = 64%). Conclusions: Beyond the limitations of this systematic review and meta-analysis (i.e., all the included studies were conducted in Asia, and using [18F]FDG PET/CT as a comparator of the index test), the quantitative data provided demonstrate the promising diagnostic performance of FAP-targeted PET imaging in GC. Nevertheless, more prospective multicentric studies are needed to confirm the excellent performances of FAP-targeted PET in this cluster of patients.

Nrf2 Downregulation Contributes to Epithelial-to-Mesenchymal Transition in Helicobacter pylori-Infected Cells.

Simple SummaryGastric cancer is mainly linked to Helicobacter pylori infection. It is therefore important to decipher the mechanisms involved in H. pylori-induced gastric carcinogenesis, and especially the early events. We have previously demonstrated that the infection leads to an epithelial-to-mesenchymal transition (EMT) favoring gastric carcinogenesis. H. pylori infection is also associated with high levels of oxidative stress. In this work, we aimed at investigating the modulation of Nrf2, a major regulator of cellular antioxidant response to oxidative stress, upon infection with H. pylori and to decipher its implication in EMT. We demonstrated that H. pylori-induced Nrf2 downregulation may participate in gastric cells’ EMT, one crucial tumorigenic event in gastric cancer. These results could pave the way for new therapeutic strategies using Nrf2 modulators to reduce gastric carcinogenesis associated with H. pylori infection.Background: Gastric cancer, the fifth most common cancer worldwide, is mainly linked to Helicobacter pylori infection. H. pylori induces chronic inflammation of the gastric mucosa associated with high oxidative stress. Our study aimed at assessing the implication of Nrf2, a major regulator of cellular redox homeostasis, in H. pylori-induced gastric carcinogenesis. Methods: Using three different gastric epithelial cell lines, a non-cancerous (HFE-145) and two different subtypes of gastric cancer (AGS and MKN74), we analyzed the modulation of Nrf2 expression over time. After invalidation of Nrf2 by CRISPR-cas9, we assessed its role in H. pylori-induced epithelial-to-mesenchymal transition (EMT). Finally, we evaluated the expression of Nrf2 and ZEB1, a central EMT transcription factor, in human gastric tissues. Results: We first demonstrated that the Nrf2 signaling pathway is differentially regulated depending on the infection stage. Rapidly and transiently activated, Nrf2 was downregulated 24 h post-infection in a VacA-dependent manner. We then demonstrated that Nrf2 invalidation leads to increased EMT, which is even exacerbated after H. pylori infection. Finally, Nrf2 expression tended to decrease in human patients’ gastric mucosa infected with H. pylori. Conclusions: Our work supports the hypothesis that Nrf2 downregulation upon H. pylori infection participates in EMT, one of the most important events in gastric carcinogenesis.

SATB1 enhances gastric cancer progression and metastasis via upregulation of CLIP4/DZIP1/ PRICKLE2 axis in gastric cancer patients

SATB1 (Special AT-rich sequence binding protein 1) plays key role in chromatin remodeling and geneexpression. SATB1 has been shown to promote invasion, migration and metastasis. However, the underlying molecular mechanisms, function and clinicopathological features of SATB1 in gastric cancer (GC) remains poorly understood. Here, we show that SATB1 plays critical role in GC progression. SATB1 upregulates in GC patients’ samples and shows co-apmlification with a subset of oncogenic proteins (PRICKLE2, ZEB1, CBWX7, WWTR1, ENAH, DZIP1, IGSF11, ZSCAN18, GFRA2, GFRA1, FGFR1, HDAC4, GHR, TIMP3, CLIP4, TAGLN and ILK) in different subtypes of GC. SATB1 shows positive correlation with GC promoting oncogenes and enhances the expression of metastasis associated genes in GC samples to potentiate GC progression. SATB1 enhances WNT/NOTCH signaling axis in GC samples. In contrast, STAB1 suppresses a network of tumor suppressor genes in GC samples. Moreover, SATB1 expression negatively correlates with GC patient’s survival. Importantly, we found that SATB1 co-amplified genes CLIP4, DZIP1 and PRICKLE2 independently involve in GC progression. Overexpression of CLIP4, DZIP1 and PRICKLE2 show poor survival rates in GC patients. DZIP1 empowers AKT3/FGF2/FGFR1 and CXCR3/CXCR6 in GC patients. PRICKLE2 enhances GC progression by targeting FGFR1/NOTCH3/WNT4 signaling. Taken together, these results identified novel roles of SATB1, CLIP4, DZIP1 and PRICKLE2 in the GC invasion, migration and metastasis using cancer bioinformatics approach. These results highlights clinical significance of SATB1, CLIP4, DZIP1 and PRICKLE2 in GC patients and furthermore, these proteins may serve as prognostic markers in GC. These results also provide SATB1, CLIP4, DZIP1 and PRICKLE2 as potential chemotherapeutic targets in treatment of gastric cancer patients.

Establishment of a Prognostic Signature of Stromal/Immune-Related Genes for Gastric Adenocarcinoma Based on ESTIMATE Algorithm.

Different subtypes of gastric cancer differentially respond to immune checkpoint inhibitors (ICI). This study aimed to investigate whether the Estimation of STromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) algorithm is related to the classification and prognosis of gastric cancer and to establish an ESTIMATE-based gene signature to predict the prognosis for patients. The immune/stromal scores of 388 gastric cancer patients from TCGA were used in this analysis. The upregulated differentially expressed genes (DEGs) in patients with high stromal/immune scores were identified. The immune-related hub DEGs were selected based on protein-protein interaction (PPI) analysis. The prognostic values of the hub DEGs were evaluated in the TCGA dataset and validated in the GSE15460 dataset using the Kaplan-Meier curves. A prognostic signature was built using the hub DEGs by Cox proportional hazards model, and the accuracy was assessed using receiver operating characteristic (ROC) analysis. Different subtypes of gastric cancer had significantly different immune/stromal scores. High stromal scores but not immune scores were significantly associated with short overall survivals of TCGA patients. Nine hub DEGs were identified in PPI analysisThe expression of these hub DEG negatively correlated with the overall survival in the TCGA cohort, which was validated in the GSE15460 cohort. A 9-gene prognostic signature was constructed. The risk factor of patients was calculated by this signature. High-risk patients had significantly shorter overall survival than low-risk patients. ROC analysis showed that the prognostic model accurately identified high-risk individuals within different time frames. We established an effective 9-gene-based risk signature to predict the prognosis of gastric cancer patients, providing guidance for prognostic stratification.

Gut microbiota of patients with different subtypes of gastric cancer and gastrointestinal stromal tumors

BackgroundGastric adenocarcinoma is associated with H. pylori infection and inflammation that can result in the dysbiosis of gastric microbiota. The association of intestinal microbiota with gastric adenocarcinoma subtypes or with gastric gastrointestinal stromal tumors (GIST) is however not well known. Therefore, we performed 16S rRNA gene sequencing on DNA isolated from stool samples of Finnish patients and controls to study differences in microbiota among different histological subtypes of gastric adenocarcinoma, gastric GIST and healthy controls.ResultsWe found that gut microbiota alpha diversity was lowest in diffuse adenocarcinoma patients, followed by intestinal type and GIST patients, although the differences were not significant compared to controls. Beta-diversity analysis however showed significant differences in microbiota composition for all subtypes compared to controls. Significantly higher abundance of Enterobacteriaceae was observed in both adenocarcinoma subtypes, whereas lower abundance of Bifidobacteriaceae was seen only in diffuse adenocarcinoma and of Oscillibacter in intestinal adenocarcinoma. Both GIST and adenocarcinoma patients had higher abundance of Enterobacteriaceae and lower abundance of Lactobacillaceae and Oscillibacter while lower abundance of Lachnoclostridium, Bifidobacterium, Parabacteroides and Barnesiella was seen only in the adenocarcinoma patients.ConclusionsOur analysis shows association of higher Enterobacteriaceae abundance with all types of gastric tumors. Therefore it could be potentially useful as a marker of gastric malignancies. Lower gut microbiota diversity might be indicative of poorly differentiated, invasive, advanced or aggressive tumors and could possibly be a prognostic marker for gastric tumors.

Molecular Network Profiling in Intestinal- and Diffuse-Type Gastric Cancer.

Simple SummaryCancer has several phenotypic subtypes where the responsiveness towards drugs or capacity of migration or recurrence are different. The molecular networks are dynamically altered in various phenotypes of cancer. To reveal the network pathways in epithelial-mesenchymal transition (EMT), we have profiled gene expression in mesenchymal stem cells and diffuse-type gastric cancer (GC), as well as intestinal-type GC. Gene expression signatures revealed that the molecular pathway networks were altered in intestinal- and diffuse-type GC. The artificial intelligence (AI) recognized the differences in molecular network pictures of intestinal- and diffuse-type GC.Epithelial-mesenchymal transition (EMT) plays an important role in the acquisition of cancer stem cell (CSC) feature and drug resistance, which are the main hallmarks of cancer malignancy. Although previous findings have shown that several signaling pathways are activated in cancer progression, the precise mechanism of signaling pathways in EMT and CSCs are not fully understood. In this study, we focused on the intestinal and diffuse-type gastric cancer (GC) and analyzed the gene expression of public RNAseq data to understand the molecular pathway regulation in different subtypes of gastric cancer. Network pathway analysis was performed by Ingenuity Pathway Analysis (IPA). A total of 2815 probe set IDs were significantly different between intestinal- and diffuse-type GC data in cBioPortal Cancer Genomics. Our analysis uncovered 10 genes including male-specific lethal 3 homolog (Drosophila) pseudogene 1 (MSL3P1), CDC28 protein kinase regulatory subunit 1B (CKS1B), DEAD-box helicase 27 (DDX27), golgi to ER traffic protein 4 (GET4), chromosome segregation 1 like (CSE1L), translocase of outer mitochondrial membrane 34 (TOMM34), YTH N6-methyladenosine RNA binding protein 1 (YTHDF1), ribonucleic acid export 1 (RAE1), par-6 family cell polarity regulator beta (PARD6B), and MRG domain binding protein (MRGBP), which have differences in gene expression between intestinal- and diffuse-type GC. A total of 463 direct relationships with three molecules (MYC, NTRK1, UBE2M) were found in the biomarker-filtered network generated by network pathway analysis. The networks and features in intestinal- and diffuse-type GC have been investigated and profiled in bioinformatics. Our results revealed the signaling pathway networks in intestinal- and diffuse-type GC, bringing new light for the elucidation of drug resistance mechanisms in CSCs.

P-148 Molecular characterisation of gastric tumours in a South Indian cohort and their clinical correlation

Gastric cancer is amongst the leading causes of cancer and cancer-related mortality worldwide. The prevalence of gastric cancer is particularly high in Eastern Asia with nearly 70 % incidence in developing countries. In this population, there remains a wide heterogenicity observed in the cancer aggressiveness and treatment outcomes, the plausible explanation being the molecular heterogenicity in gene expression and oncogenic pathways. The developments in microarray and next-generation sequencing platforms enabled the genome-scale identification of molecular dysregulations at the level of mRNA and the possible genomics-guided stratification of tumors for eventual targeted therapeutics. Numerous whole-genome profiles decoding the landscape of molecular determinants of gastric tumors have been established from Japan, South Korea, and China. However, such larger profiles of gastric tumors are largely lacking from India. This is the first comprehensive genome-wide expression landscape covering mRNA, miRNA, lncRNA, and splice variants from India. Gastric tumor samples were collected from our hospital in both liquid nitrogen and RNA later. Quality analysis was performed in Agilent Bioanalyzer 2100 using RNA 6000 Nano chips. Genome-wide expression profiling covering mRNA, miRNA, alternate splicing and lncRNA was performed using Affymetrix HTA 2.0 arrays. The dysregulated genes were compared with the profiles established from other countries. Integrative genomic analysis revealed the transcription factors OCT, NFkB, NFAT, STAT, LEF, AP, PAX, SP1, ELK1, NFYA to be up-regulated and HNF, GATA to be down-regulated in tumors. The tumour samples were then subtyped into eight different groups based on the differential activation of 21 oncogenic signaling pathways. The clinical features, intraoperative details and histopathological characteristics of the samples of the patients were collected. Patients were then followed up for a period of 2 years for recurrence and DFS was calculated. Correlation between genomic subtypes of the tumour samples and clinical outcomes/recurrence patterns were analysed. 108 patients who underwent distal gastrectomy were included in the study and genome-wide expression profiling were performed with their tumour samples. Based on the differential activation of 21 oncogenic signaling pathways, gastric cancer in this South Indian cohort could be subdivided into eight different subtypes. Among the eight subtypes, the subtype GC-1 that showed activation of differentiation-related pathways (Notch, NFAT, SP1-D, RXRA, ECM, HIF1A) was the most prevalent (n=36). The subgroup GC-7 that demonstrated no significant activation of any pathway had propensity for extranodal extension from lymph nodes when compared to the other types (p-value 0.17). Subgroup 5 and subgroup 7 had greater propensity for spread to regional lymph nodes (p-value 0.45 and 0.42, respectively). The patients belonging to subgroup 7 developed metastasis at an earlier date (p-value 0.08). Among the eight different subtypes of gastric cancer differentiated on the basis of oncogenic signaling pathway activation, the subtype GC-1 was the most prevalent, GC-7 had propensity for extranodal extension in lymph nodes and developed earlier metastasis, and subgroups GC-5 and GC-7 had a greater chance of involving regional nodes.

Prognostic value of the mRNA expression of gap junction α members in patients with gastric cancer.

Gastric cancer remains one of the primary causes of cancer-associated death worldwide. The gap junction α (GJA) family has been demonstrated to be involved in the cellular proliferation and metastasis of gastric cancer. However, the prognostic value of GJA in gastric cancer is yet to be elucidated. In the present study, the overall survival (OS) of patients with gastric cancer and the mRNA expression of GJA family members, including GJA1, GJA3, GJA4, GJA10 and GJA12, were analyzed using 593 patients with gastric cancer from the Kaplan-Meier plotter database. High GJA1 and GJA10 mRNA expression levels were associated with a poorer patient outcome (P=0.0066 and P=0.015, respectively), whereas high mRNA expression levels of GJA4 and GJA12 were associated with longer survival times (P=0.0056 and P=0.0054, respectively). Furthermore, the values of specific prognostic indicators of different subtypes of gastric cancer, including human epidermal growth factor receptor 2 status, Lauren differentiation and tumor stage, were also analyzed. The findings of the present study suggested a potential role for GJA family members in gastric cancer, which warrants further investigation.

Identifying heterogeneous subtypes of gastric cancer and subtype‑specific subpaths of microRNA‑target pathways.

The present study aimed to classify gastric cancer (GC) into subtypes and to screen the subtype-specific genes, their targeted microRNAs (miRNAs) and enriched pathways to explore the putative mechanism of each GC subtypes. The GSE13861 data set was downloaded from the Gene Expression Omnibus and used to screen differential expression genes (DEGs) in GC samples based on the detection of imbalanced differential signal algorithm. The specific genes in each subtype were identified with the cut-off criterion of U>0.04, pathway enrichment analysis was performed and the subtype-specific subpaths of miRNA-target pathway were determined. A total of 1,263 DEGs were identified in the primary gastric adenocarcinoma (PGD) samples, which were subsequently divided into four subtypes, according to the hierarchy cluster analysis. Identification of the subpaths of each subtype indicated that the subpath related to subtype 1 was miRNA (miR)-202/calcium voltage-gated channel subunit α1 (CACNA1E)/type II diabetes mellitus. The nuclear factor-κB signaling pathway was the most significantly specific pathway and subpath identified for subtype 2, which was regulated by miR-338-targeted suppression of C-C motif chemokine ligand 21 (CCL21). For subtype 3, significant related pathways included ubiquitin-mediated proteolysis and proteasome, and the important subpath was miR-146B/proteasome 26S subunit, non-ATPase 3 (PSMD3)/proteasome; focal adhesion was the significant pathway indicated for subtype 4, and the subpaths were miR-34A/vinculin (VCL)/focal adhesion and miR-34C/VCL/focal adhesion. In addition, Helicobacter pylori infection was higher in GC subtype 1 than in other subtypes. Specific genes, such as CACNA1E, CCL21, PSMD3 and VCL, may be used as potential feature genes to identify different subtypes of GC, and their associated subpaths may partially explain the pathogenetic mechanism of each GC subtype.

Large-scale molecular characterization and analysis of gastric cancer.

The recent effort by The Cancer Genome Atlas (TCGA) Network has revealed that gastric cancer, which is a leading cause of cancer-related deaths worldwide with a 5-year survival rate less than 25%, is a much more heterogeneous disease than previously thought. And yet, conventional treatment approaches and clinical trials have assumed it is a single disease. Although it is well known that under the microscope, gastric cancer cells appear quite different, the current classification scheme recognizes two main categories of gastric cancer: diffuse and intestinal. By integrating large-scale measurements of DNA, RNA, and proteins from 295 primary gastric tumors, the TCGA project found that there are four major subtypes of gastric cancer. The fact that these subtypes appear quite distinct on the molecular level suggests not only that the molecular processes driving tumorigenesis can vary among patients but also that the treatments may have to be tailored based on the subtype of tumor a patient has. This molecular stratification of patients, enabled by large-scale molecular characterization, is a significant step towards personalized therapy. The data that are generated from tumors in the TCGA project are not only very large in terms of volume, but, perhaps even more importantly, highly heterogeneous. Six different molecular analysis technologies were used for the molecular characterization of gastric cancer. These technologies provided information on DNA mutations, amplifications or deletions of gene sequences, epigenetic modifications of DNA, and levels of mRNA, microRNA, and proteins. Additionally, coded clinical information on pathology, histology, tumor characteristics, and other relevant data on each patient was collected. The computational challenge is how to integrate all this information not only to see broad differences among tumors but also to identify strong statistical associations among all these molecular and clinical data. Such associations may provide clues to how molecular systems in cancer cells are disrupted in different subtypes of gastric cancer and what treatment strategies may be most effective. For example, one of the four subtypes is characterized by the presence of the Epstein-Barr virus (EBV). Patients having tumors of this subtype tend to also have mutations in the PIK3CA pathway, extreme DNA hypermethylation, and extra copies of PD-L1 and PD-L2 genes, which are suppressors of immune response. These findings suggest that inhibitors of the PI3-K pathway may be of potential use for this subtype of gastric cancer. Further, PD-L1/2 antagonists may help promote immune destruction of the tumor. Another example of a statistical association that may have clinical use is the finding that frequent mutations in a gene called RHOA occur predominantly in the subtype of gastric cancer termed “genomically stable,” which is characterized by the lack of high levels of aneuploidy and are predominantly diffuse-type tumors. These subtypes of tumors have a higher likelihood of metastasis and are more invasive. It is known that the gene product of RHOA interacts with other proteins to alter cellular shape and motility, which are important for tumor growth. This protein or pathway may be an important therapeutic target for the genomically stable subtype of gastric cancer. The large-scale statistical analysis of the data revealed numerous other prevalent associations among factors, such as age at diagnosis, anatomic region of the stomach where the tumor occurs, gender, mutation status of genes such as TP53, and other tumor or patient characteristics. Although identifying such relationships in heterogeneous cancer data is important for the initial discovery process, much work lies ahead to functionally characterize the molecular aberrations in cancer and to develop and test effective targeted therapies. The ever-increasing volume and complexity of molecular data from cancer, exemplified by the TCGA project, calls for more sophisticated analytical approaches that can detect multivariate relationships in heterogeneous data and map that information onto the existing body of knowledge of the structure of molecular networks that govern all cellular processes. Other large-scale molecular characterization projects, such as the ENCyclopedia Of DNA Elements (ENCODE) and the Genomics of Drug Sensitivity in Cancer, are producing highly complementary data that will allow scientists to paint a more complete picture of how molecular regulatory processes are disrupted in cancer cells and what drugs may be effective in targeting a cancer's weaknesses. This first large-scale molecular characterization and analysis of gastric cancer undertaken by the TCGA project takes us one step closer toward helping patients suffering from this deadly type of cancer.

IL-1B −31T>C promoter polymorphism is associated with gastric stump cancer but not with early onset or conventional gastric cancers

It has been reported that interleukin-1beta (IL-1B) genes play a crucial role in the genetic predisposition to gastric cancer although there is no information about their role in different subtypes of gastric cancer. We performed single nucleotide polymorphism analysis of IL-1B in 241 gastric cancers including early onset gastric cancers (EOGC), conventional gastric cancers, and gastric stump cancers (GSCs) as well as 100 control patients, using real-time polymerase chain reaction and sequence analysis. The C allele was present in 60% of EOGCs, 59% of conventional gastric cancers, and 90% of GSCs, compared to 62% in the control group. Interestingly, there was no difference between early onset and conventional gastric cancer with respect to the IL-1B -31T>C polymorphism distribution. A statistically significant difference in the presence of the C allele compared to the control group was found in patients with gastric stump cancer (p = 0.008) with the T allele conferring protection against gastric stump cancer. In summary, we have shown that the IL-1B -31C allele promoter polymorphism is significantly associated with gastric stump cancer compared to the control group. Although several molecular differences have been identified between conventional gastric cancer and early onset gastric cancer, the IL-1B -31 allele distribution is similar between these two groups.

Genetic alterations and polymorphisms in gastric cancer.

The etiology of gastric cancer (GC) is multifactorial, and is likely to involve the actions of genes at multiple levels along the multistage carcinogenesis process. This article reviews the considerable progress that has been achieved in understanding the genetics of GC. The genetic effects consist of inherited genetic factors that predispose to GC, and the genetic targets of neoplastic progression that confer altered growth capacity to neoplastic cells. Inherited genotypes include germline mutations of high-penetrance genes directly associated with hereditary GC syndromes and genetic polymorphisms that indirectly affect the susceptibility to GC after exposure to carcinogens or Helicobacter pylori infection. Based on accumulation of different oncogenes or tumor suppressor genes alterations, 2 broad classes of genetic pathways called suppressor and mutator phenotypes are defined that participate in the development and progression of GC. Examples of genes involved in pathogenesis of GC include p53, adenomatous polyposis coli (APC), beta-catenin, E-cadherin, transforming growth factor (TGF)-betaRII, and hMLH1. Delineating genes involved in different subtypes of GC can reflect the heterogeneity and biologic characteristics of GC. Elucidation of the role of inherited genotypes and genetic alterations at different stages of gastrocarcinogenesis may provide a more coherent picture of the mechanism of this devastating disease and facilitate the development of novel approaches to effective prevention and intervention. Advances in high throughput technologies and functional genomics have rapidly increased our understanding of gene structure and function and its role in disease.

Association of HLA‐DQB1★0301 and HLA‐DQB1★0602 with Different Subtypes of Gastric Cancer in Taiwan

Gastric cancer (GC) is a heterogeneous disorder with multifactorial etiologies. Genetic predisposition, environmental factors, and Helicobacter pylori infection are thought to interact in the manifestation of GC. Particular human leukocyte antigen (HLA) alleles play a pivotal role in cellular immunity and may be an important genetically determined host trait. To elucidate the association between the genotype of HLA class II genes and the clinical phenotype of GC, polymorphisms of HLA‐DRB1 and HLA‐DQB1 were determined by polymerase chain reaction with sequence‐specific primers in 106 Taiwanese patients with GC and in 208 healthy controls. Comparison of allele frequencies between GC patients and healthy controls showed no significant difference at the HLA‐DRB1 locus. Patients with GC had a higher frequency of DQB1★0602 (9.4% vs. 3.6%, P<0.05, odds ratio 2.79, 95% confidence interval 1.41–5.47) and a lower frequency of DQB1★0301 (14.6% vs. 23.8%, P<0.05, odds ratio 0.55, 95% confidence interval 0.35–0.85) compared to healthy controls. Correlation of HLA‐DQB1 status with clinicopathologic features revealed predominance of male gender (16/3 vs. 50/37, P<0.05) and proximal location (12/7 vs. 28/59, P<0.05) in patients with positive HLA‐DBQ1★0602 compared to those with negative HLA‐DBQ1★0602. In contrast, a higher ratio of diffuse/intestinal subtype (20/10 vs. 30/46, P<0.05) and a lower seropositivity of Helicobacter pylori (14/30 vs. 58/76, P<0.005) were noted in patients with positive HLA‐DQB1★0301 compared to those with negative HLA‐DQB1★0301. In conclusion, HLA‐DQB1★0602 confers susceptibility to gastric cancer, especially for male Taiwanese and proximal tumor location, while HLA‐DQB1★0301 may have a protective effect on GC, probably through resistance to Helicobacter pyloriinfection. HLA‐DQB1 alleles are associated with susceptibility or resistance to GC and also influence its clinical features.