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Rare exonic minisatellite alleles in MUC2 influence susceptibility to gastric carcinoma

PLoS ONE (2007) 2(11)
DOI: 10.1371/journal.pone.0001163
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Abstract

Background. Mucins 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 Findings. We 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 melotically 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/Significance. Our 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. © 2007 Jeong et al.

Figures

  • Figure 1. Minisatellites in MUC2. A. Structure of the genomic region around MUC2. It is predicted that 49 exons (black boxes) encode MUC2. Approximate positions of minisatellites identified by the Tandem Repeats Finder Program [22], are indicated by asterisks and numbers (MS1, 2, 3, 4, 5, 6, 7, 8, 9). B. The sequences of nine minisatellite repeat units. Positions of indices (1–37,982 bp) were determined using genomic information from the UCL site [21]. doi:10.1371/journal.pone.0001163.g001
  • Figure 2. Polymorphic patterns of MUC2 minisatellites (MS1, 2, 3, 4, 6, and 8) and their Inheritance. A. Polymorphic patterns of MS1 (a), MS2 (b), MS3 (c), MS4 (d), MS6 (e), and MS8 (f). Minisatellites were PCR-amplified from genomic DNA of control samples using diagnostic primers. Allele frequency, size of PCR products and repeat number are indicated in Table S1. Haplotype patterns are numbered according to each minisatellite. Size markers (M) are given in kb (1 kb size marker) or bp (100 bp size marker). B. Meiotic inheritance of MUC2 minisatellites in a three-generation family: MS1 (a), MS2 (b), MS3 (c), MS4 (d), MS6 (e), and MS8 (f). PCR primers specific to MUC2 minisatellites were used to analyze minisatellite length in genomic DNA from family members. The pedigree demonstrates the relationship between family groups used in this study: first generation (lanes 1 and 2, grandfather and grandmother, respectively); second generation (lanes 3 and 7, fathers; lanes 4 and 8, mothers); and third generation (lanes 5 and 6, children from parents 3 and 4; lane 9, child from parents 7 and 8). M corresponds to the size marker. doi:10.1371/journal.pone.0001163.g002
  • Figure 3. MUC2 minisatellites in cancer tissues. A. Rare, cancer-specific alleles are identified in MUC2-MS6. Comparison of rare cancer-specific alleles of MUC2-MS6 between control (Figure 2A-f) and patients with gastric (a), and colon cancer (b). In patients with gastric cancer, four rare cancer-specific alleles were identified (a); and in patients with colon cancer, two rare cancer-specific alleles were identified (b). Haplotype patterns are numbered for MUC2-MS6 in gastric (a) and colon cancer (b). Rare cancer-specific alleles are indicated by arrows in (a) and (b). Size markers (M) are given in kb. B. Instability of MUC2 minisatellites in blood and cancer tissue from patients with gastric tumors. Genomic DNA was analyzed from the blood and gastric cancer tissue of patients. The sizes of minisatellites were analyzed by PCR. Results are shown for MUC2-MS2. Gastric cancer tissue samples are indicated by asterisks and M indicates the size marker. Rearrangements in cancer tissues are indicated by arrows. doi:10.1371/journal.pone.0001163.g003
  • Table 1. Frequency of rare MUC2–MS6 alleles and risk of cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
  • Table 2. Frequency of MUC2–MS6 alleles and risk of gastric cancer according to short/long tandem repeat length. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
  • Table 3. Frequency of at least one rare MUC2–MS6 allele in cancer cases and the risk of cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
  • Table 4. Age and sex distribution of cases and controls. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
  • Table 5. Tumor characteristics in cases with cancer. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Jeong, Y. H., Kim, M. C., Ahn, E. K., Seol, S. Y., Do, E. J., Choi, H. J., … Leem, S. H. (2007). Rare exonic minisatellite alleles in MUC2 influence susceptibility to gastric carcinoma. PLoS ONE, 2(11). https://doi.org/10.1371/journal.pone.0001163

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