Intragenic deletion of CDH1 as the inactivating mechanism of the wild-type allele in an HDGC tumour

Abstract

Mutations in CDH1, encoding E-cadherin, are the underlying genetic defect in approximately one-third of the hereditary diffuse gastric cancer (HDGC) families described so far. Tumours arising in these families show abnormal or absence of E-cadherin expression, following the model of tumour suppressor gene inactivation. A single study has been reported showing inactivation of the CDH1 wild-type allele in tumour cells from HDGC families either by promoter methylation or by somatic mutation. In order to find the genetic alteration responsible for the presence of diffuse gastric cancers in four members of a Caucasian family, we have screened the coding sequence of CDH1 for germline mutations and searched for the second inactivating hit in the tumour samples. In this family, we have found a germline splice-site mutation in all members affected by gastric cancer and, in one tumour, a somatic deletion affecting at least exon 8 of CDH1. Our results show that a CDH1 intragenic deletion is the second hit inactivating the wild-type allele, in one of the tumours in this family.

The NMD mRNA surveillance pathway downregulates aberrant E-cadherin transcripts in gastric cancer cells and in CDH1 mutation carriers

“…137215), an autosomal dominant syndrome characterized by high susceptibility to early onset diffuse gastric carcinomas (Guilford et al, 1998). Heterozygous carriers of E-cadherin germline mutations frequently remain asymptomatic at least until the second decade of life, when inactivation of the remaining wild-type allele of the CDH1 gene occurs (Oliveira et al, 2004). This two hit inactivation mechanism is believed to determine the initiation of diffuse gastric cancer, consistent with the two-hit inactivation model proposed by Knudson (1971).…”

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

“…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].…”

“…Aberrant E-cadherin staining patterns include absence of immunoreactivity as well as reduced membranous, "dotted" and cytoplasmic staining. The "dotted" staining pattern is probably due to the persistence of Ecadherin non-functional domains in the Golgi apparatus [51]. Abnormal immunoreactivity of E-cadherin has been described in precursor lesions (in situ SRCC and pagetoid spread of SRCs) as well as in early or advanced carcinomas, suggesting that the inactivation of Ecadherin is probably a key initiating event in HDGC tumourigenesis [60].…”

“…One report [51] described abnormal patterns of expression of both -and -catenin in early HDGCs, suggesting that the absence of a normal E-cadherin protein may lead to the disruption of the cell-cell adhesion complex. Furthermore, -actin, p120 catenin and Lin7 were shown to be reduced or absent in HDGC in another study [69].…”

“…The cell differentiation pattern of HDGC has been also investigated: Humar et al [69] described MUC5A expression in differentiated, large SRCs at the surface of gastric mucosa, and MUC6 expression in poorly differentiated cells, at the neck zone, whereas Oliveira et al [51] observed a widespread expression of gastric differentiation markers (MUC1, MUC5AC and TTF1) within the lesions.…”