Carcinogenesis Advance Access originally published online on July 1, 2004
Carcinogenesis 2004 25(11):2173-2176; doi:10.1093/carcin/bgh223
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Carcinogenesis vol.25 no.11 © Oxford University Press 2004; all rights reserved.
ARTICLE |
A functional polymorphism (–347 G
GA) in the E-cadherin gene is associated with colorectal cancer
1 Korean Hereditary Tumor Registry, Laboratory of Cell Biology, Cancer Research Institute and Cancer Research Center, Seoul National University, Korea, 2 Department of Surgery, Seoul National University Hospital, Seoul, Korea and 3 Research Institute and Hospital, National Cancer Center, Goyang, Gyeonggi, Korea
4 To whom correspondence should be addressed Email: park{at}ncc.re.kr
E-cadherin, the main adhesion molecule of epithelial cells, has been implicated in carcinogenesis because its expression is frequently lost in human epithelial cancers. E-cadherin protein expression is significantly reduced in sporadic colorectal cancers (CRC), but apparently not as a consequence of allele loss or somatic mutation. We reported recently that a single nucleotide polymorphism (–347 G
GA) in the E-cadherin promoter suppressed E-cadherin expression and was associated with familial gastric cancer. Here we sought to investigate whether the functional polymorphisms of E-cadherin might affect CRC. We genotyped 407 individuals (260 CRC patients and 147 normal controls) for the –347 GGA promoter polymorphism of E-cadherin using denaturing high-performance liquid chromatography and direct sequencing. We also measured the activity of promoters harboring the polymorphism by dual luciferase reporter assay in several CRC cell lines. We found that the E-cadherin GA genotype (G/GA heterozygous and GA homozygous) was more common in CRC patients than in normal controls (P = 0.011). Subjects with the E-cadherin GA genotype had an overall 1.75-fold increased risk of CRC. We also observed an increased risk association between the E-cadherin GA genotype and both proximal colon (P = 0.019) and distal CRC (P = 0.036). Interestingly, the GA allele decreased transcriptional efficiency by 12-, 9- and 10-fold compared with the G allele in SNU-C4, SNU-C5 and SNU-1033 cell lines, respectively. Additionally, we examined whether there was a correlation between the E-cadherin promoter polymorphism and microsatellite instability status, and found no such correlation. Taken together, our results suggest that the E-cadherin –347 GGA polymorphism may be associated with CRC.
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