Abstract
Simple SummaryE-cadherin (CDH1 gene) germline mutations are associated with the development of the autosomal cancer syndrome known as hereditary diffuse gastric cancer. About 30% of families fulfilling the clinical criteria established by the International Gastric Cancer Linkage Consortium have constitutional alterations of the CDH1 gene. Different patterns of CDH1 germline mutations have described as truncating, deletion, insertion, splice site, non sense, silence, and at last, missense alterations. The frequency of the different E-cadherin germline mutations in countries with different incidence rates for gastric carcinoma has reported extremely variable. In this study we aimed to assess the worldwide frequency of CDH1 germline mutations in gastric cancers coming from different geographical areas, using a systematic approach.Hereditary diffuse gastric cancer (HDGC) is a complex and multifactorial inherited cancer predisposition syndrome caused by CDH1 germline mutations. Nevertheless, current CDH1 genetic screening recommendations disregard an unbalanced worldwide distribution of CDH1 variants, impacting testing efficacy and patient management. In this systematic review, we collected and analyzed all studies describing CDH1 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 CDH1 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 CDH1 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 CDH1 variants conferring increased risk of gastric cancer. Herein, we demonstrate that criteria for CDH1 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.
Highlights
In the first half of the past century, GC was the most common cause of cancer-related deaths worldwide [1]
52 (4.2%) CDH1 mutations were identified in 1.224 GC patients from no criteria studies, 113 in 653 (17.3%) GCs from Hereditary diffuse gastric cancer (HDGC) criteria studies, and 22 in 670 (3.2%) early onset GCs
Identification of unexpected CDH1 due to the increasing use of multigene panels poses a challenge in GC management. We found it crucial to compile a systematic review encompassing all reports of CDH1 variants described in GC patients and analyze mutation profiles and worldwide incidence with respect to implementation of HDGC clinical criteria for genetic testing
Summary
In the first half of the past century, GC was the most common cause of cancer-related deaths worldwide [1]. In 2017 GC remained the third cause of cancer-related deaths, after lung and colorectum, with almost over 850,000 deaths globally [2]. It was the third cause of years of life lost (YLL), after lung and liver cancer [3]. Eastern Europe is the highest European risk area for GC with an incidence of 70,000 per year (Belarus area) [10]. Portugal and Italy represent relevant European areas for stomach cancer prevalence, with incidence reports around 41,100 and 33,400 per year, respectively [11]
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