Short rare MUC6 minisatellites-5 alleles influence susceptibility to gastric carcinoma by regulating gene.
The human MUC6 gene, which is reported to be expressed in the stomach and gall bladder, is clustered on chromosome 11p15.5 with other secreted mucins. In this study, the genomic structure of MUC6 has been analyzed and five VNTR (minisatellites; MS1-MS5) were identified. These minisatellites were analyzed in genomic DNA extracted from 1,103 controls, 470 gastric cancer patients, and multigenerational families. Five novel minisatellites were found to be polymorphic and transmitted through meiosis by Mendelian inheritance in families. We evaluated allelic variation in these minisatellites to determine if such variation affected the susceptibility to gastric cancer. A significant association (odds ratio [OR]=7.08) between short rare MUC6-MS5 alleles and relative risks were observed for gastric cancer (95% confidence interval [CI], 1.43-35.19; P=0.005). To investigate the function of minisatellite alleles of MUC6-MS5, we examined the effects on gene expression from luciferase reporters when inserted with minisatellites. Interestingly, when the shortest allele (7TR) was inserted in the promoter, the expression level decreased over 20-fold (P<0.001) in normal and cancer cell lines. Furthermore, the cancer-specific rare allele (TR8) also showed decreased expression levels in cancer cells. Therefore, we suggest that the short rare MUC6-MS5 alleles may be related to cancer development by the regulation of MUC6 expression.
Kwon
Jeong-Ah
JA
Department of Biology and Biomedical Science, Dong-A University, Busan 604-714, Korea.
Lee
Sang-Yeop
SY
Ahn
Eun-Kyung
EK
Seol
So-Young
SY
Kim
Min Chan
MC
Kim
Su Jin
SJ
Kim
Seung Il
SI
Chu
In-Sun
IS
Leem
Sun-Hee
SH
D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency / Q000235:genetics; D017930:Genes, Reporter; D020022:Genetic Predisposition to Disease; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats / Q000235:genetics*; D055272:Mucin-6 / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic; D012307:Risk Factors; D013274:Stomach Neoplasms / Q000235:genetics*
C524734:MUC6 protein, human; D055272:Mucin-6; D008156:Luciferases