Predictive and prognostic role of E-cadherin protein expression in patients with advanced gastric carcinomas treated with palliative chemotherapy.

Loss of E-cadherin expression has been related with an adverse outcome in patients with resected gastric cancer. More recently, experimental models with cancer cell lines showed that chemosensitivity may be affected by the E-cadherin expression status. We investigated whether E-cadherin expression is correlated with the response to chemotherapy and the survival of patients with advanced gastric cancer. Consecutive patients with advanced gastric cancer who underwent palliative chemotherapy were considered eligible for study entry. Measurable disease, complete follow-up information and availability of tumor specimens for immunohistochemistry were mandatory inclusion criteria. In 70 assessable patients, 30 patients had locoregional disease and 40 patients had visceral metastases. Chemotherapy consisted of cisplatin/fluorouracil/folinic acid in 33 patients and cisplatin/fluorouracil/epirubicin/folinic acid in 37 patients. There were 13 patients with complete response, 20 with partial response, 20 with stable disease and 17 patients progressed. Thirty-eight patients had > 80% E-cadherin-positive cancer cells (positive E-cadherin expression); 15 cases showed 25-70% (reduced E-cadherin expression), and in the remaining 17 cases E-cadherin expression was < 10% (negative E-cadherin expression). The response to chemotherapy was unrelated to the E-cadherin expression status. Conversely, survival in the 32 patients with reduced/negative E-cadherin expression (25 weeks) was significantly worse than that observed in the 38 patients with preserved E-cadherin expression (36 weeks) (p < 0.01). E-cadherin expression retained its independent prognostic role in the multivariate analysis. E-cadherin expression may give prognostic information in patients with advanced gastric cancer, but it does not seem to possess a predictive role in vivo. Some of the mechanisms inducing E-cadherin downregulation, like hypermethylation, may be potentially reversible, and they deserve further investigation as the target of novel therapeutic strategies.

The G/A nucleotide change at cDNA position 2494 in the E-cadherin gene (CDH1): analysis in Italian patients.

Current studies are investigating new E-cadherin gene (CDH1) mutations that may be responsible for diffuse gastric cancer susceptibility. Recently, a novel CDH1 germline variant presenting a G/A nucleotide change at cDNA position 2494 has been found in Japanese patients with familial diffuse gastric cancer. The consequent amino acid variation (Val/Met) may alter the binding activity to beta-catenin and the adhesive function of the E-cadherin protein. We have investigated its frequency in Italian cases of sporadic diffuse gastric cancer a well as in healthy controls. Peripheral blood samples were collected from consecutive patients with sporadic, diffuse gastric cancer and from healthy controls in the District of Urbino, Marche Region, Central Italy. After DNA extraction, standard techniques for molecular analyses were used to investigate the 2494 G/A germline nucleotide change in CDH1 cDNA. None of the 48 patients and 48 controls showed the G/A 2494 nucleotide change. Assuming a binomial distribution of the mutation among individuals and the absence of mutations in the 48 patients, the 95% upper bound for the underlying mutation frequency was 7.4%. The novel CDH1 nucleotide change is uncommon in Italian patients with sporadic diffuse gastric cancer. Given these results, further analyses in large population-based studies are not advisable.

Screening E-cadherin germline mutations in Italian patients with familial diffuse gastric cancer: an analysis in the District of Urbino, Region Marche, Central Italy.

AIMS & BACKGROUND: Hereditary diffuse gastric cancer is a recently defined cancer syndrome caused by inactivating, heterozygous germline mutations in the E-cadherin gene (CDH1). To date, 16 truncating germline CDH1 mutations have been described in hereditary diffuse gastric cancer families in different ethnic groups, but so far, no investigation has been addressed to Italian patients. In the District of Urbino, Region Marche, Central Italy, gastric cancer is the most common tumor in men and it is the second in women after breast cancer. In this area, we investigated CDH1 mutations in patients who fulfilled the hereditary diffuse gastric cancer criteria. MATERIAL AND METHODS: Consecutive patients with diffuse gastric cancer were considered eligible for the study. After pedigree analysis, patients who met the International Gastric Cancer Linkage Consortium criteria were studied for CDH1 mutations. After blood samples collection and DNA extraction, standard polymerase chain reaction and sequencing techniques were used for CDH1 analysis. RESULTS: In a study population of 98 patients with diffuse gastric cancer, 11 patients (11%) showed familial clustering and 3 of them met the International Gastric Cancer Linkage Consortium criteria for hereditary diffuse gastric cancer. None of the 3 patients showed inactivating germline mutation in CDH1. CONCLUSIONS: According to recent studies, the frequency of CDH1 inactivating germline mutations in patients who fulfil the hereditary diffuse gastric cancer criteria may be lower than that reported in early investigations. The results of the present study in a population of Italian patients seem to confirm these data. It is likely that unidentified mutations in CDH1 or other involved genes contribute to diffuse gastric cancer susceptibility.