Methylation of the E-cadherin Gene in Bladder Neoplasia and in Normal Urothelial Epithelium from Elderly Individuals

Abstract

Decreased expression of the epithelial cell adhesion protein E-Cadherin occurs in several forms of human epithelial-derived cancers, including bladder cancers.We investigated the possibility that aberrant methylation of the CpG island flanking the 5 transcriptional start site of the e-cadherin gene is responsible for the decreased expression of this gene in bladder cancer, similar to the relationship previously seen between e-cadherin methylation and gene expression in other types of human cancers. Using methylation-specific polymerase chain reaction , we found methylation of this CpG island in 20 of 47 cases (43%) of bladder neoplasms ranging from low-grade papillary neoplasms to advanced , invasive cancers. When methylation status was compared to immunochemical staining for E-Cadherin , we found significantly diminished levels of E-Cadherin expression in 14 of 15 cases (93%) with methylation of the gene. We also found decreased expression of E-Cadherin, although to a somewhat lesser extent, in a high percentage (77%) of the cases without methylation of the gene. Although these data suggest a relationship between e-cadherin CpG island methylation and decreased gene expression, it evident that other mechanisms also contribute to decreased expression of this gene in bladder neoplasia. Remarkably, we also found low levels of e-cadherin methylation in urothelial cells from three of nine (33%) histologically normal bladders, with all three of the normal bladder samples with methylated e-cadherin being from individuals older than 70 years of age. Thus, methylation of the e-cadherin CpG island may occur normally in this tissue with aging as well as in low-grade papillary neoplasms, and is not specific to cancer in the bladder. This finding of methylation in normal urothelial cells from elderly individuals is provocative with respect to a possible link between aging and increased risk for bladder cancer, but it suggests limitations on the usefulness of using methylation of e-cadherin as a molecular marker for detection of bladder cancer. (Am J Pathol 2001, 159:831-835)The E-Cadherin (E-Cad) transmembrane glycoprotein modulates calcium-dependent intercellular adhesion in a variety of epithelial tissues. The e-cadherin gene is mutated in the germline of some families with genetic predisposition to gastric cancers 1 and somatic mutations are common in lobular breast cancers and some gastric and gynecological cancers. [2][3][4] In many other common human cancers, including cancers of the breast, prostate, colon, stomach, esophagus, pancreas, thyroid, head and neck, and bladder, levels of E-Cad protein are greatly reduced compared to normal epithelial tissues. 5,6 The loss of ECad expression seems to be involved in invasive and metastatic properties of neoplastic cells, 7 consistent with the function of a tumor suppressor gene.The structure of the e-cadherin gene is notable for a dense CpG island that flanks the 5Ј transcriptional start site. Decreased expression of the e-cadherin gene has been linked to aberrant methylatio...

DNA methyltransferase 1 expression and promoter methylation of E‐cadherin in mucoepidermoid carcinoma

“…However, the aberrant gene promoter methylation cannot explain all loss of E-cadherin expression in MEC: As shown in Table 2, 4 samples without the methylated allele also were reduced for E-cadherin expression. Indeed, this phenomenon is also noted in other types of human malignancies 28,29 ; for example, the loss of E-cadherin expression in breast carcinoma occurs frequently, even in neoplasms without E-cadherin methylation. 29 This may explain the finding that E-cadherin expression may be repressed by a mechanism other than promoter hypermethylation.…”

Promoter methylation and protein expression of the E-cadherin gene in the clinicopathologic assessment of adenoid cystic carcinoma

“…22,24,[32][33][34] Moreover, methylated CpG islands of the E-cad gene were found to be frequent in non-neoplastic bladder mucosa contiguous to cancer lesions. 35 However, methylation detections from paraffin sections by MSP should carefully be interpreted in the context of intratumoral heterogeneity and field effect. We observed a discrepancy between immunoexpressions and the methylation status in some of these tumors.…”

A methylome-wide study of aging using massively parallel sequencing of the methyl-CpG-enriched genomic fraction from blood in over 700 subjects

“…The successful identification of differentially methylated regions (DMRs) associated with aging in studies of candidate loci (12)(13)(14) has stimulated interest in mapping all such sites * To whom correspondence should be addressed at: Center for Biomarker Research and Personalized Medicine, McGuire Hall, Medical College of Virginia campus, Virginia Commonwealth University, 1112 East Clay Street, Richmond, VA 23298, USA. Tel: +1 8048283428; Fax: +1 8046283991; Email: jlmcclay@vcu.edu genome-wide.…”