E-cadherin germline mutations in familial gastric cancer

Abstract

The identification of genes predisposing to familial cancer is an essential step towards understanding the molecular events underlying tumorigenesis and is critical for the clinical management of affected families. Despite a declining incidence, gastric cancer remains a major cause of cancer death worldwide, and about 10% of cases show familial clustering. The relative contributions of inherited susceptibility and environmental effects to familial gastric cancer are poorly understood because little is known of the genetic events that predispose to gastric cancer. Here we describe the identification of the gene responsible for early-onset, histologically poorly differentiated, high grade, diffuse gastric cancer in a large kindred from New Zealand (Aotearoa). Genetic linkage analysis demonstrated significant linkage to markers flanking the gene for the calcium-dependent cell-adhesion protein E-cadherin. Sequencing of the E-cadherin gene revealed a G --> T nucleotide substitution in the donor splice consensus sequence of exon 7, leading to a truncated gene product. Diminished E-cadherin expression is associated with aggressive, poorly differentiated carcinomas. Underexpression of E-cadherin is a prognostic marker of poor clinical outcome in many tumour types, and restored expression of E-cadherin in tumour models can suppress the invasiveness of epithelial tumour cells. The role of E-cadherin in gastric cancer susceptibility was confirmed by identifying inactivating mutations in other gastric cancer families. In one family, a frameshift mutation was identified in exon 15, and in a second family a premature stop codon interrupted exon 13. These results describe, to our knowledge for the first time, a molecular basis for familial gastric cancer, and confirm the important role of E-cadherin mutations in cancer.

Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA

“…Besides acting as a cell-cell interaction apparatus, E-cadherin functions as an inhibitor of the b-catenin signal by preventing the function of b-catenin as a transcriptional factor by sequestrating it to the plasma membrane. Direct connection between E-cadherin and gastric carcinogenesis has been demonstrated through the finding that genetic mutations in CDH1, the gene encoding E-cadherin, are associated with hereditary diffuse gastric cancer (Guilford et al, 1998). It is also well established that deregulated b-catenin signaling has an important function in the development of colorectal carcinoma (Segditsas and Tomlinson, 2006).…”

Helicobacter pylori CagA interacts with E-cadherin and deregulates the β-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells

“…Several lines of evidence also suggest the involvement of Ecadherin/catenin complex in gastric carcinogenesis. Germ line E-cadherin mutation is responsible for the development of hereditary diffuse-type gastric carcinoma (Guilford et al, 1998), and somatic mutations in the E-cadherin or b-catenin gene have been reported in sporadic gastric carcinoma (Berx et al, 1998). We recently reported that in vivo adaptation of cagApositive H. pylori enhances its carcinogenic potential in a rodent model (Franco et al, 2005).…”

Functional epigenetics identifies a protocadherin PCDH10 as a candidate tumor suppressor for nasopharyngeal, esophageal and multiple other carcinomas with frequent methylation

“…Downregulation of cadherins or their functional alterations have been frequently observed in human malignancies, which promotes tumor cell invasion and metastasis (Berx et al, 1995;Perl et al, 1998), suggesting that at least some cadherins can act as tumor suppressor genes (TSG). Mutations of E-cadherin (CDH1) have been reported in familial and sporadic gastric cancers and other tumors (Risinger et al, 1994;Berx et al, 1995;Guilford et al, 1998). CDH13 also has truncating mutations in tumors which lead to the deletion of transmembrane and cytoplasmic regions and disruption of its tumor suppression functions (Lee, 1996).…”