Etiology Of Gastric Cancer Research Articles

Prospective study of oral microbiome and gastric cancer risk among Asian, African American and European American populations.

Colonization of specific bacteria in the human mouth was reported to be associated with gastric cancer risk. However, previous studies were limited by retrospective study designs and low taxonomic resolutions. We performed a prospective case-control study nested within three cohorts to investigate the relationship between oral microbiome and gastric cancer risk. Shotgun metagenomic sequencing was employed to characterize the microbiome in prediagnostic buccal samples from 165 cases and 323 matched controls. Associations of overall microbial richness and abundance of microbial taxa, gene families and metabolic pathways with gastric cancer risk were evaluated via conditional logistic regression. Analyses were performed within each cohort, and results were combined by meta-analyses. We found that overall microbial richness was associated with decreased gastric cancer risk, with an odds ratio (OR) per standard deviation (SD) increase in Simpson's reciprocal index of 0.77 (95% confidence interval [CI]=0.61-0.99). Nine taxa, 38 gene families and six pathways also showed associations with gastric cancer risk at P < .05. Neisseria mucosa and Prevotella pleuritidis were enriched, while Mycoplasma orale and Eubacterium yurii were depleted among cases with ORs and 95% CIs per SD increase in centered log-ratio transformed taxa abundance of 1.31 (1.03-1.67), 1.26 (1.00-1.57), 0.74 (0.59-0.94) and 0.80 (0.65-0.98), respectively. The top two gene families (P=3.75 × 10-4 and 3.91 × 10-4 ) and pathways (P=1.75 × 10-3 and 1.53 × 10-3 ) associated with gastric cancer were related to the decreased risk and are involved in hexitol metabolism. Our study supports the hypothesis that oral microbiota may play a role in gastric cancer etiology.

TAS2R38 polymorphisms, Helicobacter pylori infection and susceptibility to gastric cancer and premalignant gastric lesions.

Gastric cancer is worldwide the fourth more common cancer type by incidence, and the third by mortality. We analyzed three missense variants of TAS2R38 gene: rs713598 (A49P), rs1726866 (V262A), and rs10246939 (I296V). These variants and their combination in haplotypes (proline, alanine and valine/tasters or alanine, valine and isoleucine/nontasters) and diplotypes are responsible for individual differences in bitter perception. The single-nucleotide polymorphisms and the related phenotypes are known to be associated with susceptibility to Gram-negative bacterial infections, such as Helicobacter pylori , and with risk of various cancer types. An association between intermediate tasters (as defined by TAS2R38 diplotypes) and increased risk of gastric cancer was reported in a Korean population. We analyzed 2616 individuals of Latin American origin, representing the whole spectrum of lesions from gastritis to gastric cancer. Comparing cancer cases vs. noncancers we observed a decrease in risk associated with heterozygous carriers of rs10246939 ( P = 0.006) and rs1726866 ( P = 0.003) when compared with homozygotes of the more common allele. Also, the analysis of diplotypes/phenotypes reflected the same association, with super-tasters showing a borderline increased risk of developing gastric cancer compared to medium-tasters [odds ratio (OR) = 1.63; 95% confidence interval (CI), 1.04-2.56; P = 0.033]. Also, nontasters showed an increased risk when compared to medium-tasters although not reaching statistical significance (OR = 1.58; 95% CI, 0.80-2.87; P = 0.203). We also tested the interactions between the TAS2R38 genotypes and H. pylori cagA status in a subset of samples and found no interaction. In conclusion, our results suggest only a modest contribution of TAS2R38 gene genetic variability in gastric cancer etiology.

Sleep duration and napping in relation to colorectal and gastric cancer in the MCC-Spain study

Sleep duration is a novel and potentially modifiable risk factor for cancer. We evaluated the association of self-reported sleep duration and daytime napping with odds of colorectal and gastric cancer. We included 2008 incident colorectal cancer cases, 542 gastric cancer cases and 3622 frequency-matched population controls, recruited in the MCC-Spain case–control study (2008–2013). Sleep information, socio-demographic and lifestyle characteristics were obtained through personal interviews. Multivariable adjusted logistic regression models were used to estimate odds ratios (OR) with 95% confidence intervals (CI) for cancer, across categories of sleep duration (≤ 5, 6, 7, 8, ≥ 9 hours/day), daytime napping frequency (naps/week) and duration (minutes/nap). Compared to 7 hours of sleep, long sleep was associated with increased odds of colorectal (OR≥9 hours: 1.59; 95%CI 1.30–1.94) and gastric cancer (OR≥9 hours: 1.95; 1.37–2.76); short sleep was associated with increased odds of gastric cancer (OR≤5 hours: 1.32; 0.93–1.88). Frequent and long daytime naps increased the odds of colorectal (OR6–7 naps/week, ≥30 min: 1.32; 1.14–1.54) and gastric cancer (OR6–7 naps/week, ≥30 min: 1.56; 1.21–2.02). Effects of short sleep and frequent long naps were stronger among participants with night shift-work history. Sleep and circadian disruption may jointly play a role in the etiology of colorectal and gastric cancer.

Identification of Helicobacter pylori in tumor biopsies obtained from patients with colorectal cancer: Indication for a prophylactic vaccine?

The association between H. pylori infection and colorectal cancer (CRC) has been controversial, and despite the undisputed roles of H. pylori in the etiology of gastric cancer, its involvement as a causative agent of CRC is unknown. We aimed to investigate the potential associations between H. pylori infection and CRC in biopsy samples taken from tumors of Iranian patients. Patients (n=49; aged 38–79 years, mean age=49) with diagnosed CRC were enrolled. Biopsies from control (n=10) and suspected CRC patients were collected from March 2017 to 1 August 2019 at the Mehrad Hospital, Tehran, Iran. The diagnosis of CRC was confirmed by pathology and colonoscopic examinations. An expert gastroenterologist performed the colonoscopic surgery and sample collection. DNA was extracted from the samples, and H. pylori infection was detected and confirmed by PCR using the glmM sequence as the species-specific gene. SPSS version 18 was used to determine the significant associations by using the two-tailed Fisher's exact test. Eighteen (46.1%) and 6 (60%) patients were female in the CRC and control groups, respectively. No significant associations were observed between H. pylori infection and family history of cancer, age, or gender. Thirty-one (79%) CRC samples showed severe inflammation. Out of the 31 CRC samples with severe inflammation, 18 (58%) were positive for H. pylori (P<0.05). We conclude that H. pylori may be involved in the CRC pathogenesis or progression. Our findings suggest that a prophylactic vaccine against H. pylori may be promising in reducing the CRC incidence.

WBP2 promotes gastric cancer cell migration via novel targeting of LATS2 kinase in the Hippo tumor suppressor pathway.

Dysregulation of signaling pathways is responsible for many human diseases. The lack of understanding of the molecular etiology of gastric cancer (GC) poses a substantial challenge to the development of effective cancer therapy. To better understand the molecular mechanisms underlying the pathogenesis of GC, which will facilitate the identification and development of effective therapeutic approaches to improve patient outcomes, mass spectrometry-based phosphoproteomics analysis was performed to map the global molecular changes in GC. A total of 530 proteins with altered phosphorylation levels were detected across a panel of 15 normal and GC cell lines. WW domain-binding protein 2 (WBP2) was validated to be upregulated in a subset of GC cell lines. WBP2 is overexpressed in 61% cases of GC compared to non-cancer tissues and high WBP2 expression correlates with poor clinical outcomes. WBP2 was found to be required for GC cell migration but is dispensable for cell growth and proliferation. WBP2 knockdown increased p-LATS2 with a concomitant increase in p-YAP, resulting in the cytoplasmic retention of YAP and ultimately the inhibition of YAP/TEAD activity and downregulation of TEAD target genes--CTGF and CYR61. Importantly, the loss of LATS2 reversed the activation of Hippo pathway caused by WBP2 knockdown, indicating that WBP2 acts through LATS2 to exert its function on the Hippo pathway. Moreover, WBP2 interacted with LATS2 to inhibit its phosphorylation and activity. In conclusion, our study established a pivotal role for WBP2 in the promotion of GC cell migration via a novel mechanism that inactivates the Hippo pathway transducer LATS2.

Risk factors for gastric cancers in the United States: Variation by anatomic site and race/ethnicity.

189 Background: Gastric cancer (GC) is a high mortality cancer in the US. Differences in risk factors by anatomic location and race/ethnicity have been suggested but remain understudied in the US population. Methods: The Multiethnic Cohort (MEC) is a prospective cohort study that collected data on 5 racial/ethnic groups [Whites (W), Blacks (B), Latino (L), Japanese-American (JA), and Hawaiian (HA)] from Hawaii and Los Angeles in 1993-1996. Participants completed a detailed baseline survey and were followed for development of incident cancer. Cox regression models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI) to identify GC risk factors by anatomic location (cardia, non-cardia) and by race/ethnicity. Results: Data from 192,626 participants was available. The cohort was 25% W, 17% B, 23% L, 28% JA, and 7% HA. During a median follow up of 20.3 years, 1,109 non-cardia and 201 cardia incident GCs were diagnosed. Older age (per year, non-cardia HR 1.08, 95% CI 1.07-1.92; cardia HR 1.06, 95% CI 1.05-1.09), male sex (non-cardia HR 1.6, 95% CI 1.4-1.8; cardia HR 3.0, 95% CI 2.1-4.4), and current (non-cardia HR 1.7, 95% CI 1.5-2.2, cardia HR 3.4, 95% CI 2.2-5.3) or former (non-cardia HR 1.3, 95% CI 1.1-1.5; cardia HR 2.0, 95% CI 1.3-2.9) smoking were associated with both cancer types. Notably, race/ethnicity (ref W: B HR 3.0, 95% CI 2.2-4.0; L HR 2.5, 95% CI 1.8-3.3; JA HR 3.9, 95% CI 3.0-5.1; HA HR 3.9, 95% CI 2.8-5.5), foreign-born (ref: self &amp; parents US born: HR 1.3 95% CI 1.1-1.7), and family history of GC (OR 1.9, 95% CI 1.5-2.3) were associated with non-cardia GC. BMI ≥30 (HR 1.6, 95% CI 1.1-2.3), having ≥1 drink/week (HR 1.6, 95% CI 1.1-2.3), and being JA (ref W: HR 1.9, 95% CI 1.2-2.9) were associated with cardia GC. Risk factors other than age differed by race/ethnicity for non-cardia GC. Male sex was a risk factor for B, L and JA only. Having less than a high school education was a risk factor for B and JA only, smoking a risk factor for L and JA only, and having diabetes a risk factor for B only. Being in the highest sodium intake quartile was a risk factor among W and HA. A family history of GC was a risk factor for W, L, and JA. Having foreign-born parents was a risk factor for W and being foreign-born was a risk factor for JA. Conclusions: GC risk factors differ between subtypes and, for non-cardia, between race/ethnic groups. These differences provide an insight into the etiology of GC and the disproportionate incidence rates in high-risk groups, potentially aiding in the design of targeted intervention strategies.

Identification of Helicobacter pylori in tumor biopsies obtained from patients with colorectal cancer: Indication for a prophylactic vaccine?

The association between H. pylori infection and colorectal cancer (CRC) has been controversial, and despite the undisputed roles of H. pylori in the etiology of gastric cancer, its involvement as a causative agent of CRC is unknown. We aimed to investigate the potential associations between H. pylori infection and CRC in biopsy samples taken from tumors of Iranian patients. Patients (n=49; aged 38–79 years, mean age=49) with diagnosed CRC were enrolled. Biopsies from control (n=10) and suspected CRC patients were collected from March 2017 to 1 August 2019 at the Mehrad Hospital, Tehran, Iran. The diagnosis of CRC was confirmed by pathology and colonoscopic examinations. An expert gastroenterologist performed the colonoscopic surgery and sample collection. DNA was extracted from the samples, and H. pylori infection was detected and confirmed by PCR using the glmM sequence as the species-specific gene. SPSS version 18 was used to determine the significant associations by using the two-tailed Fisher's exact test. Eighteen (46.1%) and 6 (60%) patients were female in the CRC and control groups, respectively. No significant associations were observed between H. pylori infection and family history of cancer, age, or gender. Thirty-one (79%) CRC samples showed severe inflammation. Out of the 31 CRC samples with severe inflammation, 18 (58%) were positive for H. pylori (P<0.05). We conclude that H. pylori may be involved in the CRC pathogenesis or progression. Our findings suggest that a prophylactic vaccine against H. pylori may be promising in reducing the CRC incidence.

Associations of Duration, Intensity, and Quantity of Smoking With Risk of Gastric Intestinal Metaplasia.

Determine whether various dimensions of smoking increase risk for gastric intestinal metaplasia. Cigarette smoking has been implicated in the etiology of gastric cancer, but it is not clear if smoking is a risk factor for gastric intestinal metaplasia, a precursor lesion of gastric cancer. We compared data from 385 gastric intestinal metaplasia cases and 1577 controls without gastric intestinal metaplasia recruited into a cross-sectional study at the Michael E. DeBakey VA Medical Center in Houston, Texas. All participants completed standardized questionnaires and underwent a study endoscopy with gastric mapping biopsies. Gastric intestinal metaplasia cases included participants with intestinal metaplasia on any noncardia gastric biopsy. We calculated odds ratios and associated 95% confidence intervals using multivariable logistic regression models. Compared with never smokers, current smokers had 2-fold increased risk for gastric intestinal metaplasia (odds ratio, 2.05; 95% confidence interval, 1.47-2.85). Among ever smokers, increasing duration and total dose were significantly associated with increased risk for gastric intestinal metaplasia (P-trend, 0.004 and 0.01, respectively). Among former smokers, risk for gastric intestinal metaplasia decreased over time and was no different to never smokers after 15 years smoking cessation. Cases with gastric intestinal metaplasia were more likely than controls to have Helicobacter pylori infection (53.2% vs. 21.7%); however, smoking effect on gastric intestinal metaplasia was not different by H. pylori infection status. Cigarette smoking is a risk factor for gastric intestinal metaplasia. Risk of gastric intestinal metaplasia among former smokers remained significantly elevated until 15 years postcessation.

Reality of Gastric Cancer in Young Patients: The Importance and Difficulty of the Early Diagnosis, Prevention and Treatment.

Gastric cancer usually arises in middle-aged to older patients, and is rarely found in younger patients. The clin-ical characteristics, etiology, prognosis, preventive methods and treatment of gastric cancer in young patients have not been fully investigated because of its low prevalence. In this review, we discuss the current under-standing and clinical problems associated with gastric cancer in young patients. Helicobacter pylori (H. pylori), which is a major cause of gastric cancer, especially in older populations, is closely associated with gastric cancer in young patients as well as in older patients. Gastric cancer in young patients tends to be diagnosed at an advanced stage with alarm symptoms. However, young patients with advanced gastric cancer tend to have a favorable general condition and organ function, so they can tolerate intensive systematic chemotherapy. Unfortunately, the prognosis of gastric cancer in young patients with an advanced stage is not favorable. We should not take this rare disease lightly, given its poor prognosis if patients are diagnosed at an unresectable stage. The evaluation of the H. pylori infection status and performance of H. pylori eradication therapy to prevent gastric cancer in young patients as well as the development of more intensive chemotherapy regimens for unre-sectable gastric cancer in young patients are warranted.

CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer.

Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.

Translational research on gastric cancer: Ruijin experience

Translational medicine refers to translating basic research achievements into the clinical application for diagnosis and treatment. There are still many issues of gastric cancer to be solved in clinical diagnosis and treatment. We need to focus on clinical questions, by means of basic research and multidisciplinary intersection approach, to further improve the overall efficacy of gastric cancer. Based on Ruijin Hospital's translational research experiences, in this paper, the authors describe the future direction in the field of translational research, such as the etiology and pathogenesis of gastric cancer, tumor markers for early diagnosis, prediction of recurrence and metastasis, classification criteria, evaluation of chemotherapy, tumor heterogeneity, targeted therapy, immunotherapy and research platform establishment. In addition, here we share our perspective of the research on serum biomarkers, specific antibodies and improvement of drug delivery for gastric cancer.

Genetic Association of Plasma Homocysteine Levels with Gastric Cancer Risk: A Two-Sample Mendelian Randomization Study.

The association of plasma homocysteine level (PHL) with gastric cancer risk was reported in observational studies. However, the causality is challenging due to confounding factors and the lack of evidence from well-designed cohort studies. Herein, we performed a two-sample Mendelian randomization (MR) analysis to investigate whether PHL is causally related to gastric cancer risk. We performed the MR analysis based on the results from genome-wide association studies consisting of 2,631 patients with gastric cancer and 4,373 controls. An externally weighted genetic risk score (wGRS) was constructed with 15 SNPs with well-established associations with PHL. We utilized logistic regression model to estimate associations of PHL-related SNPs and wGRS with gastric cancer risk in total population and in strata by sex, age, and study site, in addition to a series of sensitivity analyses. High genetically predicted PHL was associated with an increased gastric cancer risk (per SD increase in the wGRS: OR = 1.07; 95% confidence interval, 1.01-1.12; P = 0.011), which was consistent in sensitivity analyses. Subgroup analyses provided evidence of a stronger association with gastric cancer risk in women than in men. MR-Egger and weighted median regression suggested that potentially unknown pleiotropic effects were not biasing the association between PHL and gastric cancer risk. These results revealed that genetically predicted high PHL was associated with an increased gastric cancer risk, suggesting that high PHL may have a causal role in the etiology of gastric cancer. These findings provide causal inference for PHL on gastric cancer risk, suggesting a causal role of high PHL in the etiology of gastric cancer.

Analysis of the relationship between MIR155HG variants and gastric Cancer susceptibility

BackgroundGastric cancer is one of the most common cancers in the world and a major cause of cancer-related death. This study aims to determine whether genetic variations in MIR155HG could be associated with gastric cancer risk.Materials & methodsA total of 506 gastric cancer patients and 500 healthy controls were enrolled in this study. Genotypes were examined with the MassARRAY platform and data management and analysis were conducted with the Typer Software. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated with logistic regression adjusting for age and gender to evaluate the associations between SNPs with gastric cancer in genetic model analysis.ResultsThe “CC” genotype of rs4143370 decreased the risk of gastric cancer in genotype model (p = 0.020) and recessive model (p = 0.018). Inversely, the “CC” genotype of rs1893650 increased the risk of gastric cancer in genotype model (p = 0.023) and recessive model (p = 0.014). Stratified analysis showed that rs11911469 was associated with an increased risk of gastric cancer only among the male group in the dominant model (p = 0.039) and additive model (p = 0.030). The haplotype analysis showed a strong linkage disequilibrium among these six SNPs (rs4143370, rs77699734, rs11911469, rs1893650, rs34904192 and rs928883).ConclusionThis study confirmed the relationship between SNPs of MIR155HG and the gastric cancer risk among the Chinese Han population. Our data may provide a new perspective to understand the aetiology of gastric cancer.

Diosmin Regulates Oxidative Stress and Inflammatory Marker Levels in N-Methyl-N-Nitrosourea-Induced Gastric Carcinogenesis in Rats.

Gastric cancer is the most typical oncological illness globally. Though the incidence of gastric cancer has dropped dramatically over the last few years, the survival rate is yet concerning due to poor diagnostic strategy. The etiology of gastric cancer is majorly associated with dietary factors. For this reason, application of nontoxic natural agents with anticancer effects for patients is needed. Diosmin has been commonly utilized to treat various diseases both traditionally and now clinically. However, its effect on gastric carcinogenesis remains unclear. The effects of diosmin were used to evaluate how N-methyl-N-nitrosourea (MNU) induces gastric carcinogenesis in rats. The general and gross assessment of MNU in experimental animals was tabulated. Biological tumor markers (gastrin, ALP, LDH, and γ-GT) were examined. Oxidative markers (LPO) and antioxidative markers (GSH, vitamin E, and vitamin C) were determined. In addition, inflammatory cytokines (thioredoxin, glutaredoxin, NF-κB, TNF-α, IL-6, PGE2) were explored and justified with histopathological studies. Overall, the results showed positive anticancer activity demonstrated by improved body weight, reduced tumor rate, decreased oxidative marker value by increased antioxidative rate, and suppressed tumor biomarkers and inflammatory cytokines. The histopathological analysis was congruent with the data observed. Our conclusion that diosmin exerts its anticancer activity by up-regulation of antioxidants which might be responsible for amelioration of oxidative stress and inflammatory cytokines in carcinogenesis to prevent gastric cancer.

АМБИВАЛЕНТНОСТЬ ХРОНИЧЕСКОГО ВОСПАЛЕНИЯ В СЛИЗИСТОЙ ОБОЛОЧКЕ ЖЕЛУДКА

For peptic ulcer disease, the etiological role of H. pylori infection has been proven, 60-90% of gastric cancer cases are associated with H. pylori. The bacterium is recognized as a first-order carcinogen. An association has been established between the successful elimination of H. pylori and a reduced risk of gastric cancer and relapse of peptic ulcer. In the pathogenesis of chronic inflammation in the gastric mucosa associated with H. pylori, there are reference points that determine the further path of development of the pathology. If peptic ulcer is not a consequence of the direct damaging effect of NSAIDs, it is associated with the development of gastritis. In gastric ulcer, gastritis is found in both the antrum and the fundus of the stomach Atrophy of the glands begins in the antrum, then its foci are found in the fundus on the front and back walls. Gradu- ally they increase in size, merge with each other, the acid secreting zone decreases, and the border between the fundus and pyloric glands shifts in the proximal direction. With atrophic fundus gastritis, the likelihood of developing high ulcers and stomach cancer increases. Significant increase in apoptosis processes with relative rigidity of proliferation leads to the formation of ulcer, and carcinogenesis is due to excessive proliferation and accumulation of cell mutations. One of the subjects of damage is Cag A H. pylori protein, which implements remodeling of the gastric epithelial barrier. Among its effects are modulation and impaired proliferation of gastric epithelium, leading to morphological changes. The aggressive action of Cag A protein enhances toxic doses of alcohol and smoking, supporting inflammation and causing damage to the gastric mucosa. Despite the common etiology and pathogenesis of gastric ulcer and gastric cancer, the relationship with the de- velopment of atrophic pangastritis and the similarity of convention risk factors determines that the key point in the manifestation of gastric cancer is a genetic predisposition in the form of gene polymorphism causing severe atrophy as a result of chronic inflammation.

Transcriptome analysis reveals GPNMB as a potential therapeutic target for gastric cancer.

Gastric cancer has the fifth highest incidence of disease and is the third leading cause of cancer-associated mortality in the world. The etiology of gastric cancer is complex and needs to be fully elucidated. Thus, it is necessary to explore potential pathogenic genes and pathways that contribute to gastric cancer. Gene expression profiles of the GSE33335 and GSE54129 datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were compared and identified using R software. The DEGs were then subjected to gene set enrichment analysis and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Survival analyses based on The Cancer Genome Atlas database were used to further screen the essential DEGs. A knockdown assay was performed to determine the function of the candidate gene in gastric cancer. Finally, the association between the candidate gene and immune-related genes was investigated. We found that GPNMB serves as an essential gene, with a high expression level, and predicts a worse outcome of gastric cancer. Knockdown of GPNMB inhibited gastric cancer cell proliferation and migration. In addition, GPNMB may augment the immunosuppressive ability of gastric cancer by recruiting immunosuppressive cells and promoting immune cell exhaustion through PI3K/AKT/CCL4 signaling axis. Collectively, these data suggest that GPNMB acts as an important positive mediator of tumor progression in gastric cancer, and GPNMB could exert multimodality modulation of gastric cancer-mediated immune suppression.

Abstract 5051: Associations between autoimmune conditions and gastric cancer risk among elderly US adults

Abstract Background: The associations of multiple autoimmune conditions with gastric cancer may reflect their co-occurrence with autoimmune gastritis and its clinical manifestation pernicious anemia (PA), known risk factors for this malignancy. We analyzed diagnoses in US elderly aged &amp;gt;65 years to investigate the spectrum of these associations and the extent of mediation by PA. Methods: We conducted a population-based nested case-control study using the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database. 35,499 gastric cancer cases first diagnosed in SEER during 1992-2013 were compared to 200,000 cancer-free controls matched by age, sex and year of selection from a 5% random sample of Medicare beneficiaries. Autoimmune conditions were identified from inpatient Medicare claims. Logistic regression models estimated associations between autoimmune conditions and gastric cancer, as well as their direct and indirect effects on cancer risk. Results: Among 40 autoimmune conditions evaluated, four were associated with increased gastric cancer risk (odds ratio, 95% confidence interval): autoimmune hepatitis (3.32, 1.30-8.50), PA (1.94, 1.81-2.08), uveitis (1.33, 1.03-1.70) and pure red cell aplasia (1.30, 1.09-1.54). Amyotrophic lateral sclerosis was associated with decreased risk (0.23, 0.06-0.96), based on 2 gastric cancer cases vs. 47 controls with this diagnosis. Within the control population, PA was positively associated with eight other autoimmune conditions: aplastic anemia (4.45, 2.47-8.35), Crohn’s disease (3.61, 2.48-5.25), pure red cell aplasia (2.83, 2.03-3.95), polymyositis/dermatomyositis (2.82, 1.34-5.95), celiac disease (2.51, 1.24-5.08), Addison disease (2.17, 1.32-3.56), rheumatoid arthritis (1.75, 1.53-2.01) and ulcerative colitis (1.57, 1.07-2.31). Mediation analysis indicated that PA may account for 20% (p=6.52E-09) of pure red cell aplasia’s effect on gastric cancer risk. PA failed to show significant mediation of the effects of autoimmune hepatitis, uveitis and amyotrophic lateral sclerosis. Conclusions: Our study confirmed previously reported associations of PA and several other autoimmune conditions with gastric cancer risk. The association that we found between pure red cell aplasia and gastric cancer was partially mediated by PA. We also identified an intriguing set of autoimmune conditions associated with PA, many of which have been previously linked to gastric cancer; their lack of association with cancer in our data may be due to low population prevalence and insufficient statistical power. The relatively small fraction of mediation by PA does not preclude a more substantial role of subclinical autoimmune gastritis in gastric cancer etiology. Alternatively, autoimmunity may contribute through a different mechanism, perhaps via aggravation of mucosal infection by Helicobacter pylori. Citation Format: Minkyo Song, M. Constanza Camargo, Andriy Derkach, Eric A. Engels, Charles S. Rabkin. Associations between autoimmune conditions and gastric cancer risk among elderly US adults [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5051.

Epstein Barr virus antibody reactivity and gastric cancer: A population-based case-control study

BackgroundIn contrast to the recognized role of Helicobacter pylori in the etiology of non-cardia gastric cancer (GC), there is still insufficient epidemiological evidence for the involvement of Epstein-Barr virus (EBV) in gastric carcinogenesis. We aimed to evaluate the relation of antibody profile and antibody reactivity intensity against four individual EBV proteins to GC risk. MethodsWe used information from 281 GC cases and 2071 age and sex frequency matched controls recruited in the frame of the MCC-Spain multicase-control study, between 2008 and 2013. Sociodemographic, lifestyle and environmental factors were assessed in face-to-face interviews. Antibody responses to four EBV proteins (EBNA-1, ZEBRA, EA-D, and VCA-p18) were analyzed by multiplex serology. Odds ratios (OR) and 95% confidence intervals were calculated by using logistic regression mixed models to evaluate the association of seropositivity and antibody reactivity against EBV proteins with GC, adjusting for GC risk factors. Stratified analyses by tumor location (cardia vs. non-cardia) and morphology (intestinal vs. diffuse) were done. ResultsAmong controls, seropositivity for EA-D, ZEBRA, EBNA-1 and VCA-p18 was 85%, 91%, 97% and 99%, respectively. Even though seropositivity for none of the studied proteins was associated with a higher GC risk, increasing antibody reactivity against EBNA-1 and VCA-p18 was associated with higher OR of GC. This association was present for cardia and non-cardia cancer cases, and for intestinal and diffuse types. ConclusionOur results support the hypothesis that EBV may play a role in GC etiology, and highlight the importance of evaluating specific antibodies and the dose-response relations when studying widespread infections.

Smoking status and subsequent gastric cancer risk in men compared with women: a meta-analysis of prospective observational studies

BackgroundSmoking is one of the well-established risk factors for gastric cancer incidence, yet whether men are more or equally susceptible to gastric cancer due to smoking compared with women is a matter of controversy. The aim of this study was to investigate and compare the effect of sex on gastric cancer risk associated with smoking.MethodsWe conducted a systemic literature search in MEDLINE, EMBASE, and the Cochrane CENTRAL databases to identify studies published from inception to December 2018. We included prospective observational studies which reported effect estimates with 95% confidence intervals (CIs) for associations of current or former smokers with the incidence of gastric cancer by sex. We calculated the ratio of relative risk (RRR) with corresponding 95% CI based on sex-specific effect estimates for current or former smokers versus non-smokers on the risk of gastric cancer.ResultsWe included 10 prospective studies with 3,381,345 participants in our analysis. Overall, the summary RRR (male to female) for gastric cancer risk in current smokers was significantly increased compared with non-smokers (RRR: 1.30; 95% CI: 1.05–1.63; P = 0.019). Furthermore, there was no significant sex difference for the association between former smokers and gastric cancer risk (RRR: 1.20; 95% CI: 0.92–1.55; P = 0.178). However, the result of sensitivity analysis indicated the pooled result was not stable, which was altered by excluding a nested case-control study (RRR: 1.31; 95% CI: 1.10–1.57; P = 0.002).ConclusionThis systematic review showed a potential sex difference association between current smokers and the risk of gastric cancer. The sex differential in smokers can give important clues for the etiology of gastric cancers and should be examined in further studies.

Environmental etiology of gastric cancer in Iran: a systematic review focusing on drinking water, soil, food, radiation, and geographical conditions.

The aim of this systematic review study was to investigate the causal relationship between environmental factors and gastric cancer (GC) in Iran. In a narrow definition, the environment includes water, soil, air, and food. This definition was the main criterion for the inclusion of articles in this study. In addition, exposure to radiation and geographical conditions were considered as less investigated environmental factors in the literatures. International (PubMed, Web of Science, ScienceDirect, Scopus, and Cochran) and national (Scientific Information Database) databases were searched for articles on GC and environmental risk factors in Iran. Twenty-six articles were found to meet the inclusion criteria after title, abstract, and full text review. Risk factors identified for GC include consumption of red meat; high fat, fried, and salted meat; smoked, salted, and fried foods; somedairyproducts; roasted and fried seeds; strong and hot tea; and un-piped and unchlorinated drinking water, as well as exposure to radiation, loess sediment, soft and grassy soil, soil containing low concentration of molybdenum, and proximity to volcanos. Fresh fruits and vegetable, fresh fish, and honey consumption were recognized as protective agents. Given the risk factors identified, strategies to prevent GC would be educating people to choose a healthy diet and to cook and store food properly, providing access to safe drinking water, taking into account topographical and geographical conditions in choosing a right location to build residential areas, and regulating the use of radiation-emitting devices.