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Background  The frequency of E-cadherin germline mutations in countries with different incidence rates for gastric carcinoma has not been well established. The goal of this study was to assess the worldwide frequency of  CDH1  germline mutations in gastric cancers coming from low- and high-risk areas.    Methods  English articles using MEDLINE access (from 1998 to 2011). Search terms included  CDH1 , E-cadherin, germline mutation, gastric cancer, hereditary, familial and diffuse histotype.  The study included all E-cadherin germline mutations identified in gastric cancer patients; somatic mutations and germline mutations reported in other tumors were excluded.  The method of this study was scheduled in accordance with the "PRISMA statement for reporting systematic reviews and meta-analyses". Countries were classified as low- or middle/high risk-areas for gastric carcinoma incidence. Statistical analysis was performed to correlate the  CDH1  mutation frequency with gastric cancer incidence areas.    Results  A total of 122 E-cadherin germline mutations have been identified; the majority (87.5%) occurred in gastric cancers coming from low-risk areas. In high-risk areas, we identified 16 mutations in which missense mutations were predominant. (68.8%). We verified a significant association between the mutation frequency and the gastric cancer risk area ( p  < 0.001: overall identified mutations in low- vs. middle/high-risk areas).    Conclusions  E-cadherin genetic screenings performed in low-risk areas for gastric cancer identified a higher frequency of  CDH1  germline mutations. This data could open new approaches in the gastric cancer prevention test; before proposing a proband candidate for the  CDH1  genetic screening, geographic variability, alongside the family history should be considered.

Frequency of CDH1 germline mutations in gastric carcinoma coming from high- and low-risk areas: metanalysis and systematic review of the literature