Abstract
BackgroundMucins are the major components of mucus and their genes share a common, centrally-located region of sequence that encodes tandem repeats. Mucins are well known genes with respect to their specific expression levels; however, their genomic levels are unclear because of complex genomic properties. In this study, we identified eight novel minisatellites from the entire MUC2 region and investigated how allelic variation in these minisatellites may affect susceptibility to gastrointestinal cancer.Methodology/Principle FindingsWe analyzed genomic DNA from the blood of normal healthy individuals and multi-generational family groups. Six of the eight minisatellites exhibited polymorphism and were transmitted meiotically in seven families, following Mendelian inheritance. Furthermore, a case-control study was performed that compared genomic DNA from 457 cancer-free controls with DNA from individuals with gastric (455), colon (192) and rectal (271) cancers. A statistically significant association was identified between rare exonic MUC2-MS6 alleles and the occurrence of gastric cancer: odds ratio (OR), 2.56; 95% confidence interval (CI), 1.31–5.04; and p = 0.0047. We focused on an association between rare alleles and gastric cancer. Rare alleles were divided into short (40, 43 and 44) and long (47, 50 and 54), according to their TR (tandem repeats) lengths. Interestingly, short rare alleles were associated with gastric cancer (OR = 5.6, 95% CI: 1.93–16.42; p = 0.00036). Moreover, hypervariable MUC2 minisatellites were analyzed in matched blood and cancer tissue from 28 patients with gastric cancer and in 4 cases of MUC2-MS2, minisatellites were found to have undergone rearrangement.Conclusions/SignificanceOur observations suggest that the short rare MUC2-MS6 alleles could function as identifiers for risk of gastric cancer. Additionally, we suggest that minisatellite instability might be associated with MUC2 function in cancer cells.
Highlights
Mucins are high molecular weight epithelial glycoproteins that are contained in mucus, a viscous secretion that covers epithelial surfaces [1]
The degree of polymorphism within the minisatellites was examined by PCR using diagnostic primers against human genomic DNA samples isolated from cancer-free control individuals
No polymorphisms were observed in either MUC2-MS5 or MUC2MS9, which were found in introns 26 and 41, respectively
Summary
Mucins are high molecular weight epithelial glycoproteins that are contained in mucus, a viscous secretion that covers epithelial surfaces [1]. Mucin oligosaccharides are attached to the protein backbone via O-glycosidic linkages to the hydroxyl groups of serine and threonine They play an important role in the protection of epithelial cells and have been implicated in the process of epithelial renewal and differentiation [2,3]. Twenty human mucin genes have been identified and classified functionally They comprise both secreted gel-forming mucins and transmembrane mucins, some MUC gene products do not fit well into either class [1]. A statistically significant association was identified between rare exonic MUC2-MS6 alleles and the occurrence of gastric cancer: odds ratio (OR), 2.56; 95% confidence interval (CI), 1.31–5.04; and p = 0.0047. Our observations suggest that the short rare MUC2-MS6 alleles could function as identifiers for risk of gastric cancer. We suggest that minisatellite instability might be associated with MUC2 function in cancer cells
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