Mutations in Helicobacter pylori infected patients with chronic gastritis, intestinal type of gastric cancer and familial gastric cancer.

BACKGROUND: Development of sequential changes of mucous leading to gastric cancer and familial cases of gastric cancer of intestinal type is widely connected with Helicobacter pylori infections. In this study we analysed variants of genes involved in cancerogenesis and inflammatory processes of intestines in patients infected with H.pylori. Our goal was to test whether mutations in these genes predestinate to development of gastric cancer, and whether there is a genetic factor that makes it more likely for infections with H.pylori to cause gastric cancer. As infections with H. pylori are relatively common, discovering such genetic predispositions could be used for establishing risk-groups and for planning treatments. METHODS: Our studies cover analysis of variants in genes involved in cancerogenesis: TP53 (rs11540652, rs587782329, COSM10771), MSH2 (rs193922376), MLH1 (rs63750217), and inflammatory processes of intestine: NOD2 (rs2066847, rs2066842), IL1A (rs1800587) and IL1B (rs1143634) from H.pylori-infected patients. RESULTS: Mutations were more common in the group of patients with gastric cancer of intestinal type and familial cases of gastric cancer in comparison with patients with chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia or gastric cancer (p-value = 0.00824), with the prevalence of p53 mutations in patients with familial gastric cancer vs. patients with other changes of mucosa (p-value = 0.000049). Additionally, gastric cancer patients have mainly genotype TT or CT of the rs2066842 variant of the NOD2 gene. CONCLUSIONS: The lack of statistically significant changes of other interleukin genes involved in inflammatory processes may suggest the presence of H.pylori infection as a potential trigger for the development of the inflammatory process of the mucosa, leading through microbiota dysbiosis to the development of enteric gastric cancer. Mutations in analysed genes correlated with more severe mucosal changes, with a much more frequent presence of TP53 gene mutations, with a limited presence of other mutations in the familial history of gastric cancer.

Crohn's Disease Susceptibility and Onset Are Strongly Related to Three NOD2 Gene Haplotypes.

The genetic background and the determinants influencing the disease form, course, and onset of inflammatory bowel disease (IBD) remain unresolved. We aimed to determine the NOD2 gene haplotypes and their relationship with IBD occurrence, clinical presentation, and onset, analyzing a cohort of 578 patients with IBD, including children, and 888 controls. Imaging or endoscopy with a histopathological confirmation was used to diagnose IBD. Genotyping was performed to assess the differences in genotypic and allelic frequencies. Linkage disequilibrium was analyzed, and associations between haplotypes and clinical data were evaluated. We emphasized the prevalence of risk alleles in all analyzed loci in patients with Crohn disease (CD). Interestingly, c.2722G>C and c.3019_3020insC alleles were also overrepresented in ulcerative colitis (UC). T-C-G-C-insC, T-C-G-T-insC, and T-T-G-T-wt haplotypes were correlated with the late-onset form of CD (OR = 23.01, 5.09, and 17.71, respectively), while T-T-G-T-wt and C-C-G-T-wt were prevalent only in CD children (OR = 29.36, and 12.93, respectively; p-value = 0.001). In conclusion, the presence of c.3019_3020insC along with c.802C>T occurred as the most fundamental contributing diplotype in late-onset CD form, while in CD children, the mutual allele in all predisposing haplotypes was the c.2798 + 158T. Identifying the unique, high-impact haplotypes supports further studies of the NOD2 gene, including haplotypic backgrounds.

Colorectal carcinoma in the course of inflammatory bowel diseases.

BACKGROUND: Colorectal cancer (CRC) and inflammatory bowel disease (IBD) are the most prevalent diseases of the digestive system, and their association is unequivocal. A long-standing inflammatory process is one of the causes of sporadic as well as inherited cancers as it impacts on malignant transformation in a wide variety of neoplastic diseases, including colorectal cancer. METHODS: An extensive publication search was performed in Medline and PubMed database. The keywords: colorectal carcinoma, inflammation, Crohn disease, ulcerative colitis and inflammatory bowel disease were used. RESULTS: The nucleotide-binding oligomerization domain-containing protein 2 (NOD2) and toll like receptor (TLR) signaling pathways are clearly involved in the inflammatory process and are therefore implicated in the transformation of normal colonic mucosa to premalignant and malignant disease. Focal sites of inflammation could significantly increase the risk of initiation and development of cancer. Altered inflammatory activity is likely to be a result of either a disturbance of intestinal bacterial flora or an inadequate cellular response to it. Additionally, increasing the level of inflammation-related factors may also interfere with the control of cellular proliferation. CONCLUSIONS: This review shows an overview of the genetic and environmental factors that appear to influence both the occurrence of IBD and CRC with particular reference to NOD2 and TLRs as well as pro- and anti-inflammatory cytokines associated with tumor initiation and progression (encompassing both tumor invasion and metastases), as they constitute potential targets for therapeutic intervention.

DNA variants in Helicobacter pylori infected patients with chronic gastritis, dysplasia and gastric cancer.

PURPOSE: The main scope of this study was to evaluate the importance of selected DNA variants for developing inflammation of gastric mucosa and carcinogenesis in gastrointestinal diseases in patients infected with Helicobacter pylori. PATIENTS AND METHODS: Patients subjected to analysis constituted a group of 131 consecutive cases, with control groups consisting of 100 healthy volunteers and 13 dyspeptic patients. Molecular analysis included the following genes: TP53 (c.743 G > A, c.746 G > A, c.749C > T), MSH2 (c.942 + 3A > T), MLH1 (c.2041 G > A), NOD2/CARD15 (c.3016_3017insC, c.802C > T), IL1A (c.-949C > T) and IL1B (c.315C > T). DNA variants were detected using PCR-RFLP, pyrosequencing and sequencing. RESULTS: Mutations of the analyzed genes were observed more frequently in patients with a higher degree of mucosal lesions (50.9%) than in patients with milder mucosal changes (27.6%). Single mutations and polymorphisms did not affect the course of the disease. Our analysis confirms the influence of the NOD2/CARD15 c.802C > T polymorphism on the development of mucosal changes. A correlation of the frequency of the CT genotype of the NOD2/CARD15 c.802C > T polymorphism with the NOD2/CARD15 c.3016_3017insC mutation was observed. The TT genotype frequency in the c.315C > T IL1B gene polymorphism was statistically significantly higher in patients with mucosa changes. CONCLUSIONS: Accumulation of molecular abnormalities may increase the susceptibility to inflammatory response of the gastric mucosa in H. pylori-infected patients and play an important role in the development of chronic active gastritis, atrophy, intestinal metaplasia, dysplasia and the intestinal type of gastric cancer. The severity of gastric mucosal damage correlates with the presence of mutations in the gastric mucosa and the age of patients.

Interleukin-1 gene polymorphisms in chronic gastritis patients infected with Helicobacter pylori as risk factors of gastric cancer development.

Epidemiological investigations indicated association of the Helicobacter pylori infections with the occurrence of inflammatory conditions of the gastric mucosa and development of chronic gastritis and intestinal type of gastric cancer. IL1A and IL1B genes have been proposed as key factors in determining risk of gastritis and malignant transformation. The aim of this paper was to evaluate association of interleukin-1 gene polymorphisms with chronic gastritis, atrophy, intestinal metaplasia, dysplasia and intestinal type of gastric cancer in H. pylori-infected patients. Patients subjected to analysis represent group of 144 consecutive cases that suffered from dyspepsia with coexisting infection of H. pylori and chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia or gastric cancer. Molecular studies involved analysis of -889C>T polymorphism of IL1A gene and +3954C>T polymorphism of IL1B gene. Statistical analysis of association of polymorphism -889C>T of gene IL1A with changes in gastric mucosa showed lack of significance, whereas +3954C>T polymorphism of IL1B gene showed significant association. Frequency of allele T of +3954C>T polymorphism of IL1B gene was higher in group of patients with chronic gastritis, atrophy, intestinal metaplasia, dysplasia or intestinal type of gastric cancer (32.1 %) as compared with population group (23 %), χ(2) = 4.61 and p = 0.03. This corresponds to odds ratio: 1.58, 95 % CI: 1.04-2.4. Our results indicate that +3954C>T polymorphism of IL1B gene increase susceptibility to inflammatory response of gastric mucosa H. pylori-infected patients and plays a significant role in the development of chronic gastritis, atrophy, intestinal metaplasia, dysplasia and the initiation of carcinogenesis.

Association of c.802C>T polymorphism of NOD2/CARD15 gene with the chronic gastritis and predisposition to cancer in H. pylori infected patients.

This paper shows analysis of the association of the 802C>T polymorphism of the NOD2/CARD15 gene with the occurrence of the chronic inflammation of the gastric mucosa associated with the Helicobacter pylori infections, development of intestinal metaplasia and dysplasia and, in the result of this, gastric cancer. Genomic DNA samples were extracted from paraffin blocks of gastric mucosal biopsies and from peripheral blood. H. pylori infection was confirmed by histological analysis and urease test. Pyrosequencing of 802C>T polymorphism of the NOD2/CARD15 gene was performed for H. pylori infected patients (131) and population group (100). Analysis of the NOD2/CARD15 gene showed that frequency of the T allele was significantly higher (32.8%) in the group of patients in comparison with the population group (18.1%), with the relative risk of 1.8. In the patient group, the frequency of the CC genotype was 51.1%, CT 32.1% and TT 16.8% (relative risk: 0.7, 1.1 and 4.2, respectively), while in the population group it was 69.0%, 25.7% and 5.3% (relative risk: 1.0, 0.9 and 1.3, respectively). The increasing frequency of the T allele and CT and TT genotypes in the patients with increasingly deeper changes in the gastric mucosa becomes apparent. Our findings suggest that polymorphism 802C>T is associated with changes in gastric mucosa and plays a significant role in the initiation and the progression of carcinogenesis. The number of observed mutations in gastric mucosa correlated with severity of disease.