{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T18:40:34Z","timestamp":1766428834776,"version":"build-2065373602"},"reference-count":102,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,12]],"date-time":"2021-03-12T00:00:00Z","timestamp":1615507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["GR-2016-02361655"],"award-info":[{"award-number":["GR-2016-02361655"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/MED-GEN\/30356\/2017","PTDC\/BIM-ONC\/0281\/2014"],"award-info":[{"award-number":["PTDC\/MED-GEN\/30356\/2017","PTDC\/BIM-ONC\/0281\/2014"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers13061269","type":"journal-article","created":{"date-parts":[[2021,3,14]],"date-time":"2021-03-14T22:13:10Z","timestamp":1615759990000},"page":"1269","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Geographical Distribution of E-cadherin Germline Mutations in the Context of Diffuse Gastric Cancer: A Systematic Review"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9269-0146","authenticated-orcid":false,"given":"Giovanni","family":"Corso","sequence":"first","affiliation":[{"name":"Division of Breast Surgery, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy"},{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4947-9628","authenticated-orcid":false,"given":"Federica","family":"Corso","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy"}]},{"given":"Federica","family":"Bellerba","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4404-9343","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Carneiro","sequence":"additional","affiliation":[{"name":"i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7035-7422","authenticated-orcid":false,"given":"Susana","family":"Seixas","sequence":"additional","affiliation":[{"name":"i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal"}]},{"given":"Antonio","family":"Cioffi","sequence":"additional","affiliation":[{"name":"Division of Urology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1441-897X","authenticated-orcid":false,"given":"Carlo","family":"La Vecchia","sequence":"additional","affiliation":[{"name":"Department of Clinical Sciences and Community Health, University of Milan, 20133 Milan, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9208-988X","authenticated-orcid":false,"given":"Francesca","family":"Magnoni","sequence":"additional","affiliation":[{"name":"Division of Breast Surgery, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3589-2128","authenticated-orcid":false,"given":"Bernardo","family":"Bonanni","sequence":"additional","affiliation":[{"name":"Division of Cancer Prevention and Genetics, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy"}]},{"given":"Paolo","family":"Veronesi","sequence":"additional","affiliation":[{"name":"Division of Breast Surgery, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy"},{"name":"Department of Oncology and Hemato-Oncology, University of Milan, 20122 Milan, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1348-4548","authenticated-orcid":false,"given":"Sara","family":"Gandini","sequence":"additional","affiliation":[{"name":"Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), 20141 Milan, Italy"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1590-1974","authenticated-orcid":false,"given":"Joana","family":"Figueiredo","sequence":"additional","affiliation":[{"name":"i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, University of Porto, 4200-135 Porto, Portugal"},{"name":"Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1097\/CEJ.0000000000000480","article-title":"Gastric cancer: Epidemiology, biology, and prevention: A mini review","volume":"28","author":"Lyons","year":"2019","journal-title":"Eur. 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