Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer

Abstract

Aberrant promoter methylation and the associated loss of gene expression is a common accompaniment of human cancers. Nonetheless, it has been challenging to demonstrate in any given tumour that methylation of a specific gene was causal and not consequent to malignant transformation. In this regard, our attention was drawn to the genesis of gastric cancers in individuals with hereditary diffuse gastric cancer (HDGC). These individuals harbour germline mutations in the gene encoding E-cadherin, CDH1, but their cancers have consistently demonstrated absence of loss of heterozygosity at the CDH1 locus. These findings suggested the hypothesis that CDH1 promoter methylation might function as the 'second genetic hit' in the genesis of these cancers.

Histopathological, Molecular, and Genetic Profile of Hereditary Diffuse Gastric Cancer: Current Knowledge and Challenges for the Future

“…In fact, 50% of primary GC displayed CDH1 epigenetic modifications as a second-hit, whereas in GC metastases the most common second-hit was loss of heterozygosity. Different neoplastic lesions from the same patient frequently displayed different types of second-hits and different types of second-hits were also found within the same tumour sample [50,52,53]. These results demonstrated substantial heterogeneity in the mechanisms that can act as CDH1 second-hits in a single patient.…”

“…When this wild-type allele becomes inactivated by a somatic second-hit molecular mechanism, this leads to biallelic inactivation of the CDH1 gene and the development of DGC [50][51][52]. Initial reports indicated that the second-hit that inactivates CDH1 in HDGC is most commonly promoter hypermethylation [50,52]. In 2009, Oliveira et al performed a systematic study to establish the frequency of different types of somatic CDH1 second-hits occurring in CDH1-related GC [53].…”

“…The appearance of early HDGC lesions, that may or may not evolve to widely invasive carcinomas, is thought to be triggered in the stomach by the somatic inactivation of the remaining CDH1 wild-type allele [50,52,53]. Although it would be conceivable that complete CDH1 gene inactivation leads to complete loss of E-cadherin protein expression, this is not always the case.…”

Quantification of Epigenetic and Genetic 2nd Hits in CDH1 During Hereditary Diffuse Gastric Cancer Syndrome Progression

“…15,16 Data from 27 tumors arising in 27 patients from the 13 HDGC families studied so far still indicate CDH1 promoter hypermethylation as the most common 2nd-hit mechanism of inactivation. 10,11,14 In contrast with studies on the 2nd-hit inactivation mechanism of genes causing other neoplastic syndromes, [17][18][19][20] somatic genetic alterations (mutations and loss of heterozygosity [LOH]) of CDH1 were uncommonly found. 10 -12,14 As a consequence, CDH1 promoter hypermethylation has been suggested as the basis for development of early detection tools as well as for chemoprophylaxis in unaffected CDH1 mutation carriers.…”

E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines

“…Thus, in addition to its role as an invasion suppressor, E-cadherin also acts as a classical tumour suppressor gene in pre-invasive lobular breast carcinoma. Besides mutational inactivation of the E-cadherin gene, CDH1 may also be targeted by promoter hypermethylation (Graff et al, 1995;Grady et al, 2000;Tamura et al, 2000), thereby inhibiting CDH1 gene expression. Evidence is accumulating for a prominent role of epithelial-to-mesenchymal transition (EMT) in tumour progression (reviewed by Thiery, 2002).…”