Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review

Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by <i>CDH1</i> germline mutations. Nevertheless, current <i>CDH1</i> genetic screening recommendations disregard an unbalanced worldwide distribution of <i>CDH1</i> variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing <i>CDH1</i> variants in gastric cancer patients originating from both high- and low-prevalence countries. Selected studies were categorized as family study, series study, and unknown study, according to the implementation of HDGC clinical criteria for genetic testing. Our results indicate that <i>CDH1</i> mutations are more frequently identified in gastric cancer low-incidence countries, and in the family study group that encompasses cases fulfilling criteria. Considering the type of <i>CDH1</i> alterations, we verified that the relative frequency of mutation types varies within study groups and geographical areas. In the series study, the missense variant frequency is higher in high-incidence areas of gastric cancer, when compared with non-missense mutations. However, application of variant scoring for putative relevance led to a strong reduction of <i>CDH1</i> variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for <i>CDH1</i> genetic screening are critical for identification of individuals carrying mutations with clinical significance. Further, we propose that future guidelines for testing should consider GC incidence across geographical regions for improved surveillance programs and early diagnosis of disease.