title: A functional polymorphism (-347 G-->GA) in the E-cadherin gene is associated with colorectal cancer.
abstract: 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 G-->GA 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 G-->GA polymorphism may be associated with CRC.
authors.affiliation: Korean Hereditary Tumor Registry, Laboratory of Cell Biology, Cancer Research Institute and Cancer Research Center, Seoul National University, Korea.
authors.forename: Yong
authors.initials: Y
authors.lastname: Shin
authors.forename: Il-Jin
authors.initials: IJ
authors.lastname: Kim
authors.forename: Hio Chung
authors.initials: HC
authors.lastname: Kang
authors.forename: Jae-Hyun
authors.initials: JH
authors.lastname: Park
authors.forename: Hye-Won
authors.initials: HW
authors.lastname: Park
authors.forename: Sang-Geun
authors.initials: SG
authors.lastname: Jang
authors.forename: Min Ro
authors.initials: MR
authors.lastname: Lee
authors.forename: Seung-Yong
authors.initials: SY
authors.lastname: Jeong
authors.forename: Hee Jin
authors.initials: HJ
authors.lastname: Chang
authors.forename: Ja-Lok
authors.initials: JL
authors.lastname: Ku
authors.forename: Jae-Gahb
authors.initials: JG
authors.lastname: Park
mesh_terms: D000225:Adenine; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015820:Cadherins / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006147:Guanine; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012016:Reference Values
chemical_list: D015820:Cadherins; D006147:Guanine; D000225:Adenine