CDH1/E-cadherin germline mutations in early-onset gastric cancer

Abstract

Background: Gastric cancer remains a leading cause of cancer deaths worldwide. Genetic factors, including germline mutations in E-cadherin (CDH1, MIM#192090) in hereditary diffuse gastric cancer (HDGC, MIM#137215), are implicated in this disease. Family studies have reported CDH1 germline mutations in HDGC but the role of CDH1 germline mutations in the general population remains unclear. Aims: To examine the frequency of CDH1 germline mutations in a population-based series of early-onset gastric cancer (EOGC ,50 years old). Methods: 211 cases of EOGC were identified in Central-East Ontario region from 1989 to 1993, with archival material and histological confirmation of non-intestinal type gastric cancer available for 81 subjects. Eligible cases were analysed for CDH1 germline mutations by single-strand conformation polymorphism, variants were sequenced, and tumours from cases with functional mutations were stained for E-cadherin (HECD-1) using immunohistochemistry. Results: 1155 (89%) of 1296 polymerase chain reactions amplified successfully. One new germline deletion (nt41delT) was identified in a 30-year-old patient with isolated cell gastric cancer. The overall frequency of germline CDH1 mutations was 1.3% (1/81) for EOGC and 2.8% (1/36) for early-onset isolated cell gastric cancer. Conclusion: This is the first population-based study, in a lowincidence region, of genetic predisposition to gastric cancer. Combined with our previous report of germline hMLH1 mutations in two other subjects from this series, it is suggested that 2-3% of EOCG cases in North Americans may be owing to high-risk genetic mutations. These data should inform cancer geneticists on the utility of searching for specific genetic mutations in EOGC.

Identification and Characterization of CDH1 Germline Variants in Sporadic Gastric Cancer Patients and in Individuals at Risk of Gastric Cancer

“…This variant was also reported in a Finnish study [45] in 1 of 13 (7.7%) GC patients and in 2 of 51 controls (3.9%), and also in two EOGC patients of Northern American origin (3.4%) [46]. Overall data from these studies suggest that ID 2 is a quite common mutation but authors did not report data about ID 2 variant in relation to the E-cadherin expression status.…”

Comparision of the Characteristics of Familial and Sporadic Cases in Patients with Gastric Cancer

“…Recently, the molecular mechanisms underlying familial GC have been studied intensively and in last decades, GC mortality rate has decreased globally (6,8). Gastric cancer is most common encountered in men and is the second most frequently in women in Eastern Anatolia (1,9).In our daily observations, GC in has been found to be more some families.…”

Sequence analysis of the E-cadherin (CDH1) gene in a cohort of gastric cancers seen in the western cape

“…Two novel missense mutations namely; 2245C>T and 2343A>T were found to compromise cell-cell adhesion (Kaurah et al, 2007). The majority of these mutations resulted in a truncated protein which impaired the cell adhesion function (Bacani et al, 2006).…”

“…Additionally, foods containing chemicals such as nitrite compounds, low fruit and vegetable uptake is also a risk factor of the disease Other genetic factors like microsatellite instabilities, polymorphisms and germline mutations also contribute to the development of the disease. However, the prevalence of E-cadherin germline mutations ranges from 29% to 56% (Lynch et al, 2005;Bacani et al, 2006;Corso et al, 2012). Patients who do not present with germline mutations are further analysed for large genomic deletions.…”