Our study provides strong in vivo evidence that E-cadherin gene mutations may contribute to the development of diffusely growing gastric carcinomas and support a tumor/metastasis suppressor gene hypothesis.
The utility of this technique is demonstrated by PCR amplification and sequencing of the E-cadherin gene, which codes for a homophilic cell-to-cell adhesion molecule, in early gastric carcinomas of the diffuse type of Lauren's classification.
Alterations of the E (epithelial)-cadherin gene are often involved in undifferentiated-type carcinomas of the stomach, but not in the differentiated type.
To characterize the molecular features of undifferentiated-type gastric carcinomas that developed as undifferentiated-type, we examined for p53, APC, and epithelial (E)-cadherin gene mutations, microsatellite alterations including loss of heterozygosity (LOH) and microsatellite instability (MSI), and hypermethylation of the E-cadherin gene promoter in 26 early undifferentiated gastric carcinomas, consisting of 14 signet-ring cell carcinomas and 12 poorly differentiated adenocarcinomas.
The Cdh1 expression was investigated by immunostaining on archival formalin-fixed sections from 34 primary carcinomas and their accompanying normal epithelium and preinvasive and metastatic lesions.
In this study, methylation-specific polymerase chain reaction (PCR) was performed to study methylation of CpG islands in the promoters of the p16(INK4a), cadherin 1 (CDH1), and retinoic acid receptor-beta (RAR-beta) genes in 45 gastric carcinomas and to investigate whether CDH1 and RAR-beta promoter hypermethylation is associated with CIMP-positive gastric carcinoma.
Epithelial cadherin (E-cadherin) gene and protein alterations are implicated in the existence of two clearly distinct types of tumors in the stomach (isolated cell and glandular carcinomas), breast (lobular and ductal carcinomas), and thyroid (papillary and follicular carcinomas), as well as in the occurrence of poorly differentiated foci in colorectal and prostate adenocarcinomas.
In agreement with previous work demonstrating that somatic mutations and loss of heterozygosity of the E-cadherin gene are rare or absent in the majority of SCRCs studied so far, this study reports a consistent and uniform decrease or absence of E-cadherin expression, associated with aberrant methylation, in the majority of carcinomas examined, suggesting an epigenetically mediated loss of E-cadherin function in these carcinomas.
We show that a proportion of apparently sporadic early-onset diffuse gastric carcinomas are associated with germline alterations of the E-cadherin gene.
We report the absence of beta-catenin mutations in 63 sporadic colorectal carcinomas (SCRCs) with demonstrated decreased beta-catenin and E-cadherin mRNA expression and E-cadherin protein expression in a subset of carcinomas examined, suggesting that beta-catenin mutations are an extremely rare phenomenon in SCRCs and are not responsible for the transcriptional impairment of the beta-catenin/E-cadherin adhesion complex observed in these tumours.
In intestinal- and diffuse-adherent-type gastric carcinomas, we found significant associations between the presence of the CIMP and hypermethylation of several genes: hMLH1 (P = 0.006), p16(INK4a) (P = 0.018), CDH1 (P = 0.024), and RAR-beta (P = 0.044).
Hypermethylation in the CDH1 promoter region is a frequent phenomenon in poorly differentiated, diffuse gastric carcinomas and it was identified as the main mechanism for the inactivation of the remaining wild-type allele in HDGC cases.
By MSP, nearly all of the carcinomas showed aberrant methylation of E-cadherin promoter in EBVaGC (21/22), and the frequency of this aberration was significantly higher than that in EBV-negative gastric carcinoma (GC; 45/81; p = 0.0003).
CDH1 promoter hypermethylation was found in 20 out of 70 gastric carcinomas and the epigenetic change occurred in the early, as well as in the locally advanced disease.
Mutations in the epithelial cadherin (E-cadherin) gene have been shown to be associated with the occurrence of diffuse gastric carcinomas in affected families.