Risk Of Gastric Cancer Research Articles

Association between Gut Microbiota and Digestive System Cancers: A Bidirectional Two-Sample Mendelian Randomization Study.

Accumulating evidence indicates that gut microbiota closely correlates with the tumorigenesis of digestive system cancers (DSCs). However, whether the causality between gut microbiota and DSCs exists is unknown. Genome-wide association study (GWAS) summary statistics for gut microbiota and DSCs and the bidirectional two-sample Mendelian randomization (MR) analysis were utilized to assess the causality between gut microbiota and DSCs. Sensitivity analyses were performed to evaluate the robustness of our results. We found that the genus Eggerthella (OR = 0.464, 95%CI: 0.27 to 0.796, p = 0.005) was negatively associated with the risk of gastric cancer. The genetically predicted genus Lachnospiraceae FCS020 group (OR = 0.607, 95%CI: 0.439 to 0.84, p = 0.003) correlated with a lower risk of colorectal cancer, and genus Turicibacter (OR = 0.271, 95%CI: 0.109 to 0.676, p = 0.005) was a protective factor for liver cancer. In the reverse MR, DSCs regulated the relative abundance of specific strains of gut microbiota. We comprehensively screened the association between gut microbiota and DSCs using a bidirectional two-sample MR analysis and identified the causality between several microbial taxa and DSCs. Our discoveries are beneficial for the development of novel microbial markers and microbiota-modifying therapeutics for DSC patients.

Association of Helicobacter pylori Positivity With Risk of Disease and Mortality.

Helicobacter pylori colonizes the human stomach. Infection causes chronic gastritis and increases the risk of gastroduodenal ulcer and gastric cancer. Its chronic colonization in the stomach triggers aberrant epithelial and inflammatory signals that are also associated with systemic alterations. Using a PheWAS analysis in more than 8,000 participants in the community-based UK Biobank, we explored the association of H. pylori positivity with gastric and extragastric disease and mortality in a European country. Along with well-established gastric diseases, we dominantly found overrepresented cardiovascular, respiratory, and metabolic disorders. Using multivariate analysis, the overall mortality of H. pylori -positive participants was not altered, while the respiratory and Coronovirus 2019-associated mortality increased. Lipidomic analysis for H. pylori -positive participants revealed a dyslipidemic profile with reduced high-density lipoprotein cholesterol and omega-3 fatty acids, which may represent a causative link between infection, systemic inflammation, and disease. Our study of H. pylori positivity demonstrates that it plays an organ- and disease entity-specific role in the development of human disease and highlights the importance of further research into the systemic effects of H. pylori infection.

A novel adenosine signalling-based prognostic signature in gastric cancer and its association with cancer immune features and immunotherapy response.

Reliable prognostic signatures that can reflect the intrinsic characteristics of gastric cancer (GC) are still rare. Here, we developed an adenosine-based prognostic signature and explored its association with the tumour immune in GC patients, aiming at confirming the prognostic value of adenosine-related genes and guiding the GC risk stratification and immunotherapeutic response prediction. We collected adenosine pathway-related genes from STRING websites and manual searching. We enrolled the The Cancer Genome Atlas cohort and four gene expression omnibus cohorts of GC for generating and validating the adenosine pathway-based signature using the Cox regression method. Gene expression in the signature was verified using polymerase chain reaction. We also performed gene set enrichment analysis, immune infiltration assessment and immunotherapy response prediction based on this signature. Our study resulted in a six-gene adenosine signature (GNAS, CXCR4, PPP1R1B, ADCY6, NT5E and NOS3) for risk stratification of GC prognosis, with the highest area under the receiver operating characteristic curve up to 0.767 for predicting 10-year overall survival (OS). In the training cohort, patients with signature-defined high risk had significantly poorer OS than those with low risk (p < .001). Multivariate analysis identified the signature as an independent prognostic factor (hazard ratio 2.863, 95% confidence interval [1.871-4.381], p < .001). These findings were confirmed in four independent cohorts. Expression detection showed that all signature genes were upregulated in both GC tissues and cell lines. Further analysis revealed that the signature-defined high-risk patients were characterised by immunosuppressive states and associated with a poor immunotherapy response. In conclusion, the adenosine pathway-based signature represents a promising risk stratification tool for GC in guiding individualised prognostication and immunotherapy.

Endoscopic evaluation by the Kyoto classification of gastritis combined with serum anti-Helicobacter pylori antibody testing reliably risk-stratifies subjects in a population-based gastric cancer screening program.

We previously demonstrated that the Kyoto classification of gastritis was useful for judging the status of Helicobacter pylori infection in a population-based screening program, and that adding H. pylori antibody test improved its accuracy (UMIN000028629). Here, we tested whether our endoscopic diagnosis of H. pylori infection status reliably estimated gastric cancer risk in the program. Data were collected from1345 subjects who underwent endoscopic follow-up 4years after the end of the registration. We analyzed the association of three diagnostic methods of H. pylori infection with gastric cancer detection: (1) endoscopic diagnosis based on the Kyoto classification of gastritis; (2) serum diagnosis according to the ABC method (H. pylori antibody and pepsinogen I and II); and (3) endoscopic diagnosis together with H. pylori antibody test. During the follow-up, 19 cases of gastric cancer were detected. By Kaplan-Meier analysis, the detection rates of cancer were significantly higher in the past or current H. pylori infection groups than in the never-infected group with all 3 methods. By the Cox proportional hazards model, the hazard ratio for cancer detection was highest in evaluation with the combined endoscopic diagnosis and the antibody test (method 3; hazard ratio 22.6, 95% confidence interval 2.99-171) among the three methods (the endoscopic diagnosis (method 1); 11.3, 2.58-49.8, and the ABC method (method 2); 7.52, 2.49-22.7). Endoscopic evaluation of H. pylori status with the Kyoto classification of gastritis, especially combined with serum anti-Helicobacter pylori antibody testing, reliably risk-stratified subjects in a population-based gastric cancer screening program.

Functional Annotation and Gene Set Analysis of Gastric Cancer Risk Loci in a Korean Population.

We aimed to identify the associated single nucleotide polymorphisms (SNPs) with gastric cancer (GC) risk by genome-wide association study (GWAS) and to explore the pathway enrichment of implicated genes and gene-sets with expression patterns. The study population was comprised of 1,253 GC cases and 4,827 controls from National Cancer Center and an urban community of the Korean Genome Epidemiology Study and their genotyping was performed. SNPs were annotated, and mapped to genes to prioritize by three mapping approaches by functional mapping and annotation (FUMA). The gene-based analysis and gene-set analysis were conducted with full GWAS summary data using MAGMA. Gene-set pathway enrichment test with those prioritized genes were performed. In GWAS, rs2303771, a nonsynonymous variant of KLHDC4 gene was top SNP associated significantly with GC (odds ratio, 2.59; p=1.32×10-83). In post-GWAS, 71 genes were prioritized. In gene-based GWAS, seven genes were under significant p < 3.80×10-6 (0.05/13,114); DEFB108B had the lowest p=5.94×10-15, followed by FAM86C1 (p=1.74×10-14), PSCA (p=1.81×10-14), and KLHDC4 (p=5.00×10-10). In gene prioritizing, KLDHC4 was the only gene mapped with all three gene-mapping approaches. In pathway enrichment test with prioritized genes, FOLR2, PSCA, LY6K, LYPD2, and LY6E showed strong enrichment related to cellular component of membrane; a post-translation modification by synthesis of glycosylphosphatidylinositol (GPI)-anchored proteins pathway. While 37 SNPs were significantly associated with the risk of GC, genes involved in signaling pathways related to purine metabolism and GPI-anchored protein in cell membrane are pinpointed to be playing important role in GC.

History of Various Classifications of Gastritis

Gastritis is common worldwide. The combination of Helicobacter pylori (H. pylori) infection with background gastritis, including atrophic gastritis or intestinal metaplasia is implicated as an important etiopathogenetic contributor to gastric cancer. Since the gastritis classification proposed by Schindler, research has focused on classification of gastritis for accurate diagnosis and prediction of prognosis. Advances in endoscopic technology have enabled more accurate visualization of the gastric mucosa and ‘targeted’ biopsies with the emergence of newer classifications based on visual findings (Kimura-Takemoto classification) and more specific histopathological findings using targeted biopsies (Whitehead classification). Following the discovery of H. pylori, it is mandatory to consider its role as an important contributor to gastritis. Therefore, it was necessary to redefine the classification of gastritis and arrive at a consensus, which led to the establishment of an international consensus classification, referred to as the Sydney system. However, the Sydney system alone cannot predict the gastric cancer risk, and scoring systems such as the Operative Link for Gastritis Assessment and the Operative Link on Gastritis Assessment based on Intestinal Metaplasia were proposed. These systems are based on histopathological findings observed in endoscopic biopsy specimens. However, availability of high-definition images following technological advances has facilitated the emergence of a visual classification, the Kyoto classification. In contrast to the Sydney system, the Kyoto classification is based exclusively on interpretation of visual findings and focuses on detection of H. pylori infection and gastric cancer prediction. In this review, we summarize the history and background of the various classifications of gastritis.

Type A, Type B, and Non-atrophic Gastritis

The gastric cancer risk varies based on the etiology and severity of gastritis, which depends on a history of Helicobacter pylori infection and the secretory capacity of the stomach. Type A gastritis is associated with reverse atrophy of the corpus and type B with progressive atrophy extending from the antrum to the corpus. Diffuse or spotty redness in the corpus together with high serum pepsinogen (PG) II levels and a low PG I/II ratio are observed in patients with H. pylori infection when secretory capacity of the stomach is intact. Diffuse-type gastric cancer may develop near the gastric folds, which is a rare site of atrophy. Low serum PG I levels are associated with progressive gastric corpus atrophy and intestinal metaplasia in patients with chronic and previous H. pylori infections. This clinical scenario predisposes patients to intestinal-type gastric cancer, which originates in the atrophic and metaplastic gastric mucosa. Conversely, a high PG I/II ratio is observed in patients without H. pylori infection. Serum PG I levels and the PG I/II ratio are high in patients with acute H. pylori-negative gastritis, including drug-induced gastritis but are significantly low in autoimmune gastritis. Gastric neuroendocrine tumors may develop in patients with autoimmune gastritis or in those with long-term acid suppressant use. Fasting serum gastrin levels and the risk of neuroendocrine tumors are high in both cases. In this review, types of gastritis are summarized along with evaluation performed to determine the secretory capacity of the background gastric mucosa.

Prophylactic immunization to Helicobacter pylori infection using spore vectored vaccines.

Helicobacter pylori infection remains a major public health threat leading to gastrointestinal illness and increased risk of gastric cancer. Mostly affecting populations in developing countries no vaccines are yet available and the disease is controlled by antimicrobials which, in turn, are driving the emergence of AMR. We have engineered spores of Bacillus subtilis to display putative H. pylori protective antigens, urease subunit A (UreA) and subunit B (UreB) on the spore surface. Following oral dosing of mice with these spores, we evaluated immunity and colonization in animals challenged with H. pylori. Oral immunization with spores expressing either UreA or UreB showed antigen-specific mucosal responses (fecal sIgA) including seroconversion and hyperimmunity. Following challenge, colonization by H. pylori was significantly reduced by up to 1-log. This study demonstrates the utility of bacterial spores for mucosal vaccination to H. pylori infection. The heat stability and robustness of Bacillus spores coupled with their existing use as probiotics make them an attractive solution for either protection against H. pylori infection or potentially for therapy and control of active infection.

Supplement use and gastric cancer risk in the Southern Community Cohort Study.

Gastric cancer remains a racial health disparity in the US, but few studies have examined supplements as a potential protective factor. We examined associations between regular supplement use and gastric cancer risk among the predominantly Black participants in the Southern Community Cohort Study (SCCS). Of the 84,508 individuals recruited in the SCCS from 2002 to 2009, 81,884 responded to the baseline question: any vitamin or supplement taken at least once per month in the past year. Secondary analyses assessed specific supplement use. Associations with incident gastric cancer were examined using adjusted Cox proportional hazards models, stratified by histologic subtype and secondarily by healthy eating index (HEI). Approximately half of the participants (47%, n = 38,318) reported any regular supplement use. Among the 203 incident gastric cancers over the follow-up period (median, 7years), 142 were non-cardia (NCGC), 31 cardia (CGC), and 30 unknown. Regular supplement use was associated with a 30% decreased risk of NCGC (hazards ratio (HR) 0.70; 95% confidence interval (CI) 0.49-0.99). Among participants below the HEI median, any regular supplement and multivitamin use were associated with a 52% and 70% decrease in risk of NCGC (HR 0.48; 95%CI 0.25-0.92 and HR 0.30; 95%CI 0.13-0.71), respectively. No associations were found for CGC. Regular supplement use, including multivitamins, was associated with a decreased risk of NCGC in the SCCS, particularly among participants with a lower quality diet. Inverse associations of supplement use and NCGC incidence provide support for clinical trials among high-risk populations in the US.

EBV antibody and gastric cancer risk: a population-based nested case-control study in southern China

BackgroundWe aim to clarify the controversial associations between EBV-related antibodies and gastric cancer risk.MethodsWe analysed the associations between serological Epstein-Barr nuclear antigen 1 immunoglobulin A (EBNA1-IgA) and viral capsid antigen immunoglobulin A (VCA-IgA) by enzyme-linked immunosorbent assay and the risk of gastric cancer in a nested case-control study originated from a population-based nasopharyngeal carcinoma (NPC) screening cohort in Zhongshan, a city of southern China, including 18 gastric cancer cases and 444 controls. Conditional logistic regression was used to calculate the odds ratios (ORs) and corresponding 95% confidence intervals (CIs).ResultsAll the sera of cases were sampled before diagnosis and the median time interval was 3.04 (range: 0.04, 7.59) years. Both increased relative optical density (rOD) values of EBNA1-IgA and VCA-IgA were associated with higher risks of gastric cancer with age adjusted ORs of 1.99 (95%CI: 1.07, 3.70) and 2.64 (95%CI: 1.33, 5.23), respectively. Each participant was further classified as high or medium/low risk based on a combination of two anti-EBV antibody levels. Participants in the high-risk group had substantially higher odds of developing gastric cancer than that in the medium/low risk group with an age adjusted OR of 6.53 (95%CI: 1.69, 25.26).ConclusionsOur research reveals positive associations between EBNA1-IgA and VCA-IgA and gastric cancer risk in southern China. We thus postulate that EBNA1-IgA and VCA-IgA might appear to be potential biomarkers for gastric cancer. More research to further validate the results among diverse populations and investigate its underlying biological mechanism is needed.

Genetic risk and gastric cancer: polygenic risk scores in population-based case-control study

ABSTRACT Objective This study aimed to screen and identify common variants and long noncoding RNA (lncRNA) single nucleotide polymorphisms (SNPs) associated with gastric cancer risk, and construct prediction models based on polygenic risk score (PRS). Methods The risk factors associated with gastric cancer were screened following meta-analysis and bioinformatics, verified by population-based case-control study. We constructed PRS and weighted genetic risk scores (wGRS) derived from the validation data set. Net reclassification improvement (NRI), integrated discrimination improvement (IDI), Akaike information criterion (AIC) and Bayesian information criterion (BIC) were used to evaluate model. Results The PRS was divided into 10 quantiles, with the 40–60% quantile as a reference. A risk gradient was revealed across quantile of the PRS, the risk of gastric cancer in the highest 10 quantile of PRS was 3.24-fold higher than that in control population (OR = 3.24, 95%CI: 2.07, 5.06). For NRI and IDI, PRS combinations were significantly improved compared to wGRS model combinations (P < 0.001). The model of PRS combined with lncRNA SNPs, smoking, drinking and Helicobacter pylori infection was the best-fitting model (AIC = 117.23, BIC = 122.31). Conclusion The model based on PRS combined with lncRNA SNPs, H. pylori infection, smoking, and drinking had the optimal predictive ability for gastric cancer risk, which was helpful to distinguish high-risk groups.

Clinical Application of the Kyoto Classification of Gastritis

Recent advances in endoscopic technology, including high-definition and image-enhanced endoscopy such as narrow-band imaging have facilitated close observation and detailed imaging of the gastric mucosa. Currently, endoscopy is performed in Korea primarily for evaluation of premalignant conditions and gastric cancer detection. Recent research has established the Kyoto classification of gastritis, a novel grading system for endoscopic gastritis, which enables prediction of Helicobacter pylori (H. pylori) infection. The Kyoto classification score is calculated based on the sum of scores for five main items (of 19 endoscopic findings indicative of H. pylori infection) such as atrophy, intestinal metaplasia, enlarged gastric folds, nodularity, and diffuse redness with/without regular arrangement of collecting venules (RAC). Of these five endoscopic findings, atrophy, intestinal metaplasia, enlarged gastric folds, and nodularity are associated with an increased risk and RAC with a decreased risk of gastric cancer. Previous studies have reported that a Kyoto classification score ≥2 indicates current or past H. pylori infection. An increase in the Kyoto classification score is associated with a high risk of gastric cancer; specifically, a Kyoto classification score ≥4 indicates a high risk of gastric cancer. However, H. pylori eradication is followed by disappearance of enlarged gastric folds, nodularity, and diffuse redness; therefore, this grading system cannot accurately reflect the gastric cancer risk in patients with previous H. pylori infection. Limited studies have discussed the Kyoto classification of gastritis in Korea. Therefore, further large-scale multicenter studies are warranted for validation of the Kyoto classification to predict H. pylori infection and gastric cancer risk.

The significance of endoscopic Kyoto classification of gastritis in the gastric cancer risk assessment: A systematic review and meta‑analysis.

Kyoto Classification of Gastritis is a newly proposed gastric cancer risk assessment in recent years. It selects important gastroscopic manifestations that have been reported and calculates score values. Although it has been extensively employed in clinical practice, there is no thorough review or systematic summary of its usage. We looked for works published before May 2022 on the correlation between the Kyoto Classification of Gastritis and gastric cancer (GC) risk in Web of Science, EMBASE, China National Knowledge Infrastructure, PubMed, Wanfang database, and other suitable sources. Statistical analysis was carried out using Stata 14.0 and RevMan 5.40. Two statistical methods were employed. Eight case-control studies involving 6927 patients (continuous variables group: 1961 patients; dichotomy variables group: 4966 patients) were included, and the meta-analysis results showed a significant association between Kyoto Classification of Gastritis and GC. A Kyoto classification score ≥ 4 might indicate a risk of GC (odds ratios 7.30; 95% confidence intervals [CI] 3.62-14.72; P < .00001. There was a significant difference between gastritis and GC scores (mean difference [MD] 0.86; 95% CI 0.73-0.99; P < .00001). Moreover, we found that intestinal metaplasia and atrophy highly affected the Kyoto Classification score (MD = 0.35, MD = 0.72 95% CI 0.20-0.50,0.56-0.88). However, there was considerable heterogeneity in both statistical analyses. We found the source of heterogeneity in the first analysis method but failed to find it in the second analysis method, which may be due to the small number of studies. The Kyoto Classification of gastritis score is crucial for detecting early stomach cancer. A score >4 suggests a significant risk for gastric cancer, with atrophy and intestinal metaplasia having the most impact. This score may be promoted at primary hospitals; however, because of the small number and quality of included studies, the results mentioned above need to be verified by randomized control trials with large samples and high-quality methods.

P-130 Phylogeography origin of Helicobacter pylori isolated from Colombian patients with different risk of gastric cancer

P-130 Phylogeography origin of Helicobacter pylori isolated from Colombian patients with different risk of gastric cancer

Impact of PIWIL1 Single Nucleotide Polymorphisms on Gastric Cancer Risk in a Chinese Population.

Background: PIWI-like proteins contribute to the onset and progression of carcinogenesis. Whether single nucleotide polymorphisms (SNPs) in the PIWI-like 1 (PIWIL1) gene affect the morbidity and mortality of gastric cancer (GC) remains unclear. To investigate the efficacy of PIWIL1 SNPs genotype on the morbidity and mortality of GC and its interaction within PIWIL1 gene SNPs variation and between elevated plasma glucose. Materials and Methods: We conducted a case-control study that contained 216 GC patients and 204 cancer-free controls to compare differential expression of PIWIL1 SNPs. Results: PIWIL1 gene rs1106042 AA and AG genotypes were associated with significantly reduced GC risk (odds ratio [OR]: 0.15 and 0.26, p < 0.001 and p = 0.016), and rs10773771 CT+CC type significantly increased cancer risk (OR: 1.54 p = 0.037). We observed strong associations between rs10773771 and pathological type (p = 0.012), rs11703684, and invasion depth (p = 0.012). We noticed significant gene-gene interaction between rs1106042 and rs10773771 (p = 0.0107). Interaction between the copresence of rs1106042 GG plus hyperglycemia was also significant (relative excess risk due to interaction: 28.78, attributable proportion due to interaction: 68.2%, synergy index: 3.32). Patients with rs1892723 TT and rs1892722 GG+GA type had better survival (p = 0.030 and p = 0.048). Conclusion: rs10773771 CT+CC was associated with GC risk increase, rs1106042 AA and AG function as a protective factor. rs1892723 CT+TT and rs1892722 AA type may portend a poor prognosis. Elevated fasting plasma glucose will significantly increase the risk of PIWIL gene rs1106042 GG carcinogenesis by multiplicative interaction.

CDH1 and hereditary diffuse gastric cancer: a narrative review

Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome that increases lifetime risk of diffuse-type gastric cancer which carries a dismal overall survival. Due to the high prevalence of cancer in patients with CDH1 variants, early screening and prophylactic total gastrectomy (PTG) are recommended. This review aims to summarize the current understanding of CDH1 and HDGC, highlighting its molecular and cellular implications as well as its clinical management and research efforts.A review of PubMed and ClinicalTrials.gov was conducted. Articles published in English and with full text were considered. PubMed was searched using the terms 'CDH1' AND 'Hereditary Diffuse Gastric Cancer'.Loss-of-function mutations in the CDH1 gene, which encodes the cell adhesion protein E-cadherin, have been identified as the primary cause of HDGC. The loss of E-cadherin expression disrupts cell-cell adhesion and activates oncogenic signaling pathways, ultimately promoting cancer cell growth and dissemination. Prophylactic total gastrectomy (PTG) is recommended for pathogenic CDH1 variant carriers with a family history of diffuse gastric cancer (DGC). However, recent studies of endoscopic surveillance utilizing specific biopsy protocols have demonstrated the potential for surveillance as an alternative to total gastrectomy in selected patients. Researchers are actively investigating the consequences of E-cadherin loss in gastric epithelium and have identified potential molecular drivers of HDGC development using animal models and organoids. These discoveries provide promise for chemoprevention strategies, biomarker discovery, and targeted therapies for diffuse-type gastric cancer.The understanding of HDGC has significantly advanced in recent years, with the loss of E-cadherin expression identified as a crucial factor in disease pathogenesis. The use of advanced in vitro models offers substantial promise for investigating the molecular mechanisms underlying HDGC and identifying novel therapeutic targets. By leveraging advanced models, continuing clinical trials, and improving clinical management of affected individuals, researchers can work towards the development of more effective treatment strategies for HDGC. The goal is to prevent cancers from developing in patients with CDH1 gene variants and minimize the burden of cancer.

P-134 Biomolecules with potential inhibitor of Helicobacter pylori isolated from patients with high risk of gastric cancer in Colombia

P-134 Biomolecules with potential inhibitor of Helicobacter pylori isolated from patients with high risk of gastric cancer in Colombia

P-133 Human susceptibility biomarkers associated to gastric cancer risk in Colombia populations

P-133 Human susceptibility biomarkers associated to gastric cancer risk in Colombia populations

P-414 Gastric cancer risk factors knowledge in Mexican population. LEGACy 3A

P-414 Gastric cancer risk factors knowledge in Mexican population. LEGACy 3A

Dissecting the genetic heterogeneity of gastric cancer.

Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. German Research Foundation (DFG).