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

Abstract

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.

Keywords: CDH1 mutation; E-cadherin; cancer geographical distribution; gastric cancer.

Figure 1

Scheme illustrating the study design. Articles nr. 228 were excluded if not original (reviews), were reports of somatic studies (not germline), or not associated with gastric cancer (i.e., lobular breast, ovarian, colon, cancers).

Figure 2

Relative frequency of CDH1 mutation types. For each study group, the relative frequency of deletions, insertions, as well as non-sense, missense and splice-site alterations is represented in the graph. Percentages were calculated based on the total number of mutations found in each study group. The series study group includes 187 mutations, the family study one 356, and the unknown study group encompasses 20 mutations.

Figure 3

CDH1 mutation worldwide distribution. Representation of relative frequencies of the different CDH1 mutation types within the European, American, Asian and Oceania continents, in the settings of either the series study (A) or the family study (B) groups.

Figure 4

CDH1 missense mutation distribution based upon variant scoring. The relative frequency of the different missense variant categories was evaluated in continents displaying higher missense variant frequencies. (A) Series study, (B) Family study.