[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-353524-105":59,"doc-detail-353524-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","the-changing-landscape-of-hereditary-diffuse-gastric-cancer","The Changing Landscape of Hereditary Diffuse Gastric Cancer","","Hereditary diffuse gastric cancer (HDGC) is a dominantly inherited cancer syndrome marked by early-onset diffuse gastric cancer and lobular breast cancer. It is mainly driven by germline truncating CDH1 mutations encoding E-cadherin, with less frequent predisposing CTNNA1 mutations encoding α-catenin. Disease initiation involves inactivation of pathogenic alleles, promoting intramucosal signet ring cell carcinomas that can progress toward invasive growth. Clinical care combines endoscopic surveillance and prophylactic total gastrectomy, with attention to variant effects, diagnostic strategy, and emerging classification and management research.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/the-changing-landscape-of-hereditary-diffuse-gastric-cancer/353524/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/the-changing-landscape-of-hereditary-diffuse-gastric-cancer/353524.png","ImageObject",300,407,{"name":92,"@type":93},"Patrick","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-27","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What genetic mutations primarily cause hereditary diffuse gastric cancer (HDGC)?","Question",{"text":112,"@type":113},"HDGC is predominantly caused by germline truncating mutations in CDH1, which encodes E-cadherin. Less frequent predisposing mutations occur in CTNNA1, which encodes α-catenin.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does HDGC develop at the initiation step in mutation carriers?",{"text":117,"@type":113},"The first step involves inactivation of wildtype CDH1 or CTNNA1 alleles in carriers, leading to intramucosal gastric signet ring cell carcinomas (SRCCs).",{"name":119,"@type":110,"acceptedAnswer":120},"How is HDGC managed clinically?",{"text":121,"@type":113},"Management uses an increasingly balanced approach combining endoscopic surveillance with prophylactic total gastrectomy for most carriers of pathogenic/likely pathogenic CDH1 variants, while also accounting for elevated lobular breast cancer risk in female carriers.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},353524,1790137484,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":81,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},549758146520,"https://ap-avatar.wpscdn.com/avatar/80002397d8c0411e94?_k=1775819394049821470","J Gastric Cancer. 2026 Jan;26(1):31-51 [https://doi.org/10.5230/jgc.2026.26.e5](https://doi.org/10.5230/jgc.2026.26.e5)[ ](https://doi.org/10.5230/jgc.2026.26.e5)pISSN 2093-582X·eISSN 2093-5641  \nReview Article  \nReceived: Dec 9, 2025  \nAccepted: Dec 12, 2025  \nPublished online: Dec 26, 2025  \nCorrespondence to  \nParry Guilford  \nCancer Genetics Laboratory, Department of Biochemistry, University of Otago, 710 Cumberland Street, Dunedin North, Dunedin 9016, New Zealand.  \nEmail: [parry.guilford@otago.ac.nz](parry.guilford@otago.ac.nz)  \n*Conor Vaessen and Kieran Redpath contributed equally to this work.  \nCopyright © 2026. Korean Gastric Cancer Association  \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ([https://](https://)[ ](https://)[creativecommons.org/licenses/by-nc/4.0](creativecommons.org/licenses/by-nc/4.0)) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.  \nORCID iDs  \nKieran Redpath  [https://orcid.org/0000-0002-2221-7038](https://orcid.org/0000-0002-2221-7038)[ ](https://orcid.org/0000-0002-2221-7038)Emily Schulpen  [https://orcid.org/0009-0009-5514-2907](https://orcid.org/0009-0009-5514-2907)[ ](https://orcid.org/0009-0009-5514-2907)Parry Guilford  [https://orcid.org/0000-0002-7256-9576](https://orcid.org/0000-0002-7256-9576)  \nFunding  \nThis study was supported by New Zealand Health Research Council  \n(HRC, 22/301), No Stomach for Cancer ([www.nostomachforcancer.org](www.nostomachforcancer.org)) and Save Our Stomachs ([www.saveourstomachs.org](www.saveourstomachs.org)) .  \nThe Changing Landscape of Hereditary Diffuse Gastric Cancer  \nConor Vaessen*, Kieran Redpath  *, Emily Schulpen , Parry Guilford   \nCancer Genetics Laboratory, Department of Biochemistry, University of Otago, Dunedin, New Zealand  \nABSTRACT  \nHereditary diffuse gastric cancer (HDGC) is a dominantly inherited cancer syndrome characterized by the early onset of diffuse gastric cancer (DGC) and lobular breast cancer. HDGC is predominantly caused by germline truncating mutations in CDH1, which encodes the cell–cell adhesion protein, E-cadherin. Less frequent predisposing mutations are observed in the CTNNA1 gene that encodes α-catenin. E-cadherin and α-catenin are components of the epithelial adherens junction and play important roles in cell adhesion, signal transduction, and cell architecture maintenance. The first step in DGC initiation in carriers of pathogenic CDH1 and CTNNA1variants is the inactivation of wildtype CDH1 or CTNNA1alleles, leading to the development of intramucosal gastric signet ring cell carcinomas (SRCCs) . In the case ofCDH1 mutations, E-cadherin loss is associated with abnormal orientation of the mitotic spindle, which is believed to result in the displacement of dividing stem or progenitor cells out of the epithelial plane and into either the glandular lumen or lamina propria. Although these early stage pT1a SRCCs are generally indolent, they can acquire aggressive traits that precede a pattern of invasive growth. HDGC is clinically managed using an increasingly balanced approach involving endoscopic surveillance and prophylactic total gastrectomy. In this review, we discuss the range of predisposing germline HDGC variants and their effects, the mechanism of DGC initiation and growth, and current best practices for the diagnosis and management of this disease. Finally, we highlight emerging areas of research on the characterization, classification, and management of HDGC.  \nKeywords: Cadherins; Catenins; Signet ring cell carcinoma; Gastrectomy; Neoplastic syndromes  \nINTRODUCTION  \nHereditary diffuse gastric cancer (HDGC) is a rare cancer syndrome first described following the identification of germline mutations in the CDH1 genes of 3 large Māori families from Aotearoa New Zealand. Each of these families had a multigenerational history of early onset diffuse gastri","cbCaijWFc1opAWcr","https://ap.wps.com/l/cbCaijWFc1opAWcr","pdf",2588903,21,"English","# Abstract\n# Introduction\n# Genetics and Clinical Presentation of HDGC\n## Predisposing HDGC Mutations\n# Conflict of Interest\n# Author Contributions","[{\"question\":\"What genetic mutations primarily cause hereditary diffuse gastric cancer (HDGC)?\",\"answer\":\"HDGC is predominantly caused by germline truncating mutations in CDH1, which encodes E-cadherin. Less frequent predisposing mutations occur in CTNNA1, which encodes α-catenin.\"},{\"question\":\"How does HDGC develop at the initiation step in mutation carriers?\",\"answer\":\"The first step involves inactivation of wildtype CDH1 or CTNNA1 alleles in carriers, leading to intramucosal gastric signet ring cell carcinomas (SRCCs).\"},{\"question\":\"How is HDGC managed clinically?\",\"answer\":\"Management uses an increasingly balanced approach combining endoscopic surveillance with prophylactic total gastrectomy for most carriers of pathogenic/likely pathogenic CDH1 variants, while also accounting for elevated lobular breast cancer risk in female carriers.\"}]","The Changing Landscape of Hereditary Diffuse Gastric Cancer | PDF",1790105903,53]