MUC1 gene polymorphism in the gastric carcinogenesis pathway (original) (raw)
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European Journal of Human Genetics, 2003
Gastric cancer (GC) stands as the second most common cause of cancer death for males worldwide, and intestinal metaplasia (IM) is a lesion that precedes GC development. In previous works it was shown that polymorphisms of MUC1 gene are associated with increased risk for GC and IM. The aim of the present study was to evaluate MUC1 gene polymorphism in patients with chronic gastritis from Colombia. A Portuguese population of patients with chronic gastritis was used for comparative purposes. A total of 67 Colombian cases and 52 Portuguese cases were analysed by restriction analysis and Southern blotting. MUC1 allele frequencies were significantly different between the two populations, with an overall prevalence of smaller alleles in Colombian samples. Colombian cases showed a lower prevalence of individuals homozygous for small MUC1 mucins in cases without IM (62.5%) when compared with cases with IM (86.0%). The same trend, although not statistically significant, is observed in the Portuguese population. In conclusion, our study shows that Colombian patients with chronic gastritis have a significantly higher prevalence of small MUC1 alleles than the Portuguese population. Our study also shows that small MUC1 genotypes are associated with increased risk for IM development in Colombian patients.
Risk of gastric cancer is associated with the MUC1 568 A/G polymorphism
International journal of oncology, 2009
Identifying the genetic variants that alter MUC1 protein expression may further our understanding of the risk for development of gastric cancer (GC). We used PCR-SSPs to identify the genotype of MUC1 A/G polymorphism at its 568 site of exon 2 and immunohistochemistry to detect MUC1 protein expression in GC patients and non-cancer subjects and analyzed the association between this polymorphism and MUC1 protein expression. We found that the frequency of AA genotype was significantly high in the GC patients and the risk for GC in AA genotype carriers increased 1.81-fold. Moreover, we found a significant underexpression of MUC1 protein in GC as compared to non-cancer subjects, which was negatively correlated to AA genotype of MUC1 (r=-0.1790, P=0.004). Furthermore, this study provides a possible mechanistic insight that the MUC1 A/G polymorphism at its 568 site disrupts the physiological functions of MUC1 which is important to the physiological protection of gastric mucosa. Thus we have...
Annals of Human Genetics, 1999
MUC1 is a highly polymorphic mucin type glycoprotein expressed on the surface of many epithelia, including gastric mucosa, and is present in several body fluids and mucous secretions. A genetic polymorphism due to variation in length of a 60 bp tandemly repeated sequence domain constitutes more than half of the coding region of the glycoprotein. We demonstrated previously in a Portuguese population sample that the frequency of small MUC1 alleles is increased in patients with gastric carcinoma, suggesting that the possession of small MUC1 alleles confers increased risk for gastric carcinoma development. This finding raised the possibility that the very high prevalence of gastric carcinoma in Portugal could be partly due to a high frequency of small MUC1 alleles in the Portuguese population. In the present study we compared the MUC1 allele distribution in a population of Danish blood donors with the distribution in a population of Portuguese blood donors. The frequency of small MUC1 alleles was significantly higher in the Danish than in the Portuguese sample, thus failing to lend support to the hypothesis that a relatively higher frequency of the small MUC1 alleles might account for the high prevalence of gastric carcinoma in Portugal when compared to Denmark.
Carcinogenesis, 2012
In order to assess whether inherited genetic variability in the mucin genes associates with the evolution of gastric cancer precursor lesions (GCPLs), we genotyped 22 tagSNPs in MUC1, MUC6 and MUC2 genes of 387 patients with GCPLs that had been followed up for 12.8 years. According to the diagnosis at recruitment and at the end of follow-up, the lesions did not change in 43.1% of the patients, regressed in 28.7% and progressed in 28.2%. Three SNPs in the 3#moiety of MUC2 were significantly associated with a decreased risk of progression of the lesions, whereas another four SNPs, located at the 5#-moiety, were found to be significantly associated either with increased [one single-nucleotide polymorphism (SNP)] or decreased (three SNPs) probability of regression. Stratified analysis indicated that significance was maintained only in those subjects positive for Helicobacter pylori infection and in those not consuming non-steroidal anti-inflammatory drugs, which were found protective against lesion progression. Haplotype analyses indicated the presence of two haplotypes, one in each moiety of the gene, that were significantly associated with decreased risk of progression of the lesions [odds ratio (OR) 5 0.49 and 0.46; 95% confidence interval (CI) 5 0.28-0.85 and 0.25-0.86, respectively]. The 5#-end haplotype was also associated with increased probability of regression (OR 5 1.67; 95% CI 5 1.02-2.73), altogether suggesting a protective role against progression of the precancerous lesions. No significant association was found with variants in MUC1 and MUC6 genes. These results indicate, for the first time, that genetic variability in MUC2 is associated with evolution of GCPLs, especially in H.pylori infected patients, suggesting a role of this secreted mucin in gastric carcinogenesis.
PSCA and MUC1 Gene Polymorphisms Are Linked with Gastric Cancer and Pre-malignant Gastric Conditions
Anticancer Research, 2014
Background/Aim: Genome-wide association studies revealed a link between gastric cancer (GC) and single nucleotide polymorphisms (SNPs) of prostate stem cell antigen (PSCA), phospholipase C epsilon-1 (PLCE1) and mucin-1 (MUC1) genes. Herein, we aimed to evaluate associations between PSCA (C>T, rs2294008; G>A, rs2976392), MUC1 (C>T, rs4072037) and PLCE1 (A>G, rs2274223) SNPs and GC or high-risk gastritis (HRAG). Materials and Methods: Using TaqMan system, SNPs were genotyped in 252 patients with GC, 136 patients with HRAG and 246 controls. Results: PSCA rs2294008 allele T was linked with risk of GC (odds ratio (OR)=1.88, p<0.001) and HRAG (OR=1.49, p=0.009). Allele A of PSCA rs2976392 was associated with development of GC (OR=1.88, p<0.001) and HRAG (OR=1.56, p<0.01). MUC1 rs4072037 allele G was protective against development of GC (OR=0.64, p=0.0005), while no differences were found for PLCE1 rs2274223. Conclusion: Polymorphisms of PSCA (rs2976392, rs2294008) and MUC1 (rs4072037) genes are linked with GC and HRAG. Gastric cancer (GC) is one of the most common causes of cancer-related death worldwide (1). Most recent reports on cancer reveal a declining incidence of GC in Western countries; nevertheless, the mortality associated with GC remains very high (1). The pathways of GC pathogenesis have merged into a complex picture, which involves Helicobacter pylori infection as well as genetic, epigenetic and other co-founding factors (2). A genome-wide association study (GWAS) approach has been applied in various diseases including cancer. The first GWAS on GC was published in 2008 and identified an association with a single nucleotide polymorphism (SNP) of prostate stem cell antigen (PSCA) gene (3). A few GWAS studies confirmed this association and revealed new susceptibility loci at mucin-1 (MUC1) and phospholipase C epsilon-1 (PLCE1) genes (3, 4). Gene SNPs detected in the aforementioned GWAS studies have been implicated in various cancer-related molecular pathways. PSCA gene encodes a cell membrane glycoprotein responsible for cellular activation (3). PSCA gene is expressed in the epithelium of the stomach and it is particularly down-regulated in gastric tissue with intestinal metaplasia (3). MUC1 gene encodes a cell membrane protein that plays a role in forming protective mucous barriers on stomach epithelial surfaces and is essential in intracellular signaling (5). Different studies have shown that MUC1 is involved in the regulation of H. pylori-induced chronic gastritis (5). PLCE1 gene encodes an enzyme that catalyzes hydrolysis which generates second messengers affecting the cell cycle (6). The PLCE1-related signaling network has an impact on several critical carcinogenetic processes, including proliferation, cell survival, metabolism, and tumor growth (6). The changes of encoding sequences of these genes have functional roles and may influence the process of carcinogenesis.