Molecular alterations of E-cadherin gene: possible role in human bladder carcinogenesis.
E-cadherin is a transmembrane glycoprotein which mediates a calcium dependent homophilic interaction among epithelial cells. The altered expression and gene mutations of E-cadherin adhesion molecule have been frequently observed in various tumors. Several invasive carcinomas showed cell-cell adhesion loss although the tumor cells expressed considerable amounts of E-cadherin protein. The purpose of this study was to evaluate the role of E-cadherin gene alterations in genesis and progression of bladder carcinoma by mutation analysis of coding region, expression analysis and microsatellite instability at E-cadherin chromosome locus. We analyzed 30 bladder carcinoma (28 transitional and 2 squamous cell carcinoma) at different stage and grade. The mutation analysis showed that in one case there was a presence of a point mutation at codon 846 that consisted of a G (AGC) to C (ACC) transversion resulting in the replacement of R to T. In another sample the sequence analysis revealed a same-sense mutation at the codon 785 (AAC - AAT). The study of E-cadherin mRNA by Northern blot analysis showed that there were no differences of mRNA levels between tumor and normal mucosa samples. We noted that invasive and anaplastic tumors showed a trend to loss of expression, even if we did not find any statistically significant differences. The microsatellite analysis showed the presence of genomic instability in proximity of the E-cadherin gene. Nine out of 30 (30%) specimens presented molecular alterations in at least one out of 2 loci (D16S260 and D16S301) analyzed. The comparison between microsatellite mutations and clinical-histopathological parameters revealed a higher number of alterations in invasive respect to superficial tumors (p=0.014). On the other hand, there were no statistical differences regarding the correlation with pathological grade. These observations, which, nevertheless, need to be confirmed in a larger number of patients, suggest that alterations of E-cadherin gene may be related to pathobiology of bladder cancer development and clinical progression.
Taddei
I
I
Medical Genetics Unit, Department of Clinical Physiopathology, Florence University Medical School, Florence, Italy.
Piazzini
M
M
Bartoletti
R
R
Dal Canto
M
M
Sardi
I
I
D000368:Aged; D000369:Aged, 80 and over; D019943:Amino Acid Substitution; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009367:Neoplasm Staging; D018807:Polymorphism, Single-Stranded Conformational; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001749:Urinary Bladder Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology
D015820:Cadherins; D012333:RNA, Messenger