{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:37:53Z","timestamp":1791607073697,"version":"4.3.4"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T00:00:00Z","timestamp":1749427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hereditary diffuse gastric and lobular breast cancer (HDGLBC) is an inherited cancer syndrome predominantly characterized by diffuse gastric cancer (DGC) and lobular breast cancer (LBC). LBC often serves as the initial manifestation of HDGLBC, even in the absence of DGC symptoms. Despite advancements in medical technology and treatment, gastric cancer remains a major health burden globally. Approximately 1%\u20133% of gastric cancers are attributed to hereditary cancer syndromes, with pathogenic variants in the CDH1 gene being a significant contributor. CDH1 encodes E-cadherin, a protein essential for cell\u2013cell adhesion in epithelial tissues. CDH1 inactivation through germline mutations leads to a high risk of developing DGC and LBC. The inactivation process involves a \u2018second hit\u2019 mechanism, commonly promoter methylation, leading to the loss of E-cadherin expression and subsequent tumorigenesis. Additionally, mechanisms such as loss of heterozygosity and somatic mutations contribute to CDH1 inactivation. Current research highlights the complexity of these mechanisms and their role in HDGLBC pathogenesis. Therapeutic strategies targeting these pathways, including epigenetic drugs and synthetic lethal approaches, show promise in restoring CDH1 function and inhibiting tumor progression. Given the aggressive nature of HDGLBC, early diagnosis and personalized treatment plans are crucial. Surveillance for LBC in CDH1 mutation carriers should be prioritized, considering prophylactic mastectomy and chemoprevention. This narrative review highlights the need for understanding the genetic and epigenetic alterations in HDGLBC, which provide critical insights for developing effective therapies and improving patient outcomes. Further research is necessary to refine these strategies and explore novel therapeutic targets.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf092","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T02:59:41Z","timestamp":1749437981000},"page":"1345-1352","source":"Crossref","is-referenced-by-count":10,"title":["Second-hit <i>CDH1<\/i> gene mechanisms in hereditary diffuse gastric and lobular breast cancer syndrome: frequency and impact on tumorigenesis"],"prefix":"10.1093","volume":"34","author":[{"given":"Giovanni","family":"Corso","sequence":"first","affiliation":[{"name":"Division of Breast Surgery, European Institute of Oncology, IRCCS , via Ripamonti, 435 - 20141 - Milan ,","place":["Italy"]},{"name":"Department of Oncology and Hematology, University of Milano , via Ripamonti, 435 - 20141 - Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Magnoni","sequence":"additional","affiliation":[{"name":"Division of Breast Surgery, European Institute of Oncology, IRCCS , via Ripamonti, 435 - 20141 - Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Dal Molin","sequence":"additional","affiliation":[{"name":"Clinic Unit of Oncogenomics, IEO, IRCCS , via Ripamonti, 435 - 20141 - Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Marino","sequence":"additional","affiliation":[{"name":"Clinic Unit of Oncogenomics, IEO, IRCCS , via Ripamonti, 435 - 20141 - Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Nicosia","sequence":"additional","affiliation":[{"name":"Division of Breast Imaging, European Institute of Oncology, IRCCS , via Ripamonti, 435 - 20141 - Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Pesapane","sequence":"additional","affiliation":[{"name":"Division of Breast Imaging, European Institute of Oncology, IRCCS , via Ripamonti, 435 - 20141 - Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas M","family":"Noonan","sequence":"additional","affiliation":[{"name":"MultiMedica, IRCCS , Via Milanese, 300, 20099 Sesto San Giovanni - Milan ,","place":["Italy"]},{"name":"Department of Biotechnology and Life Sciences, University of Insubria , Via J.H. Dunant 3 - 21100 - Varese ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adriana","family":"Albini","sequence":"additional","affiliation":[{"name":"European Institute of Oncology, IRCCS , via Ripamonti, 435 - 20141 - Milan ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,6,9]]},"reference":[{"key":"2025081901162604500_ref1","doi-asserted-by":"publisher","first-page":"e247862","DOI":"10.1001\/jamanetworkopen.2024.7862","article-title":"CDH1 genotype exploration in women with hereditary lobular breast cancer phenotype","volume":"7","author":"Corso","year":"2024","journal-title":"JAMA Netw Open"},{"key":"2025081901162604500_ref2","doi-asserted-by":"crossref","first-page":"25","DOI":"10.21037\/cco-23-36","article-title":"CDH1 and hereditary diffuse gastric cancer: a narrative review","volume":"12","author":"Gregory","year":"2023","journal-title":"Chin Clin Oncol"},{"key":"2025081901162604500_ref3","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.3389\/fphar.2018.01421","article-title":"CDH1 gene and hereditary diffuse gastric cancer syndrome: molecular and histological alterations and implications for diagnosis and treatment","volume":"9","author":"Luo","year":"2018","journal-title":"Front Pharmacol"},{"key":"2025081901162604500_ref4","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13058-015-0517-z","article-title":"Lobular breast cancer: molecular basis, mouse and cellular models","volume":"17","author":"Christgen","year":"2015","journal-title":"Breast Cancer Res"},{"key":"2025081901162604500_ref5","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13058-020-01384-6","article-title":"Invasive lobular carcinoma of the breast: the increasing importance of this special subtype","volume":"23","author":"McCart Reed","year":"2021","journal-title":"Breast Cancer Res"},{"key":"2025081901162604500_ref6","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.891426","article-title":"Case report: male lobular breast cancer in hereditary cancer syndromes","volume":"12","author":"Carnevali","year":"2022","journal-title":"Front Oncol"},{"key":"2025081901162604500_ref7","doi-asserted-by":"crossref","first-page":"e386","DOI":"10.1016\/S1470-2045(20)30219-9","article-title":"Hereditary diffuse gastric cancer: updated clinical practice guidelines","volume":"21","author":"Blair","year":"2020","journal-title":"Lancet Oncol"},{"key":"2025081901162604500_ref8","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1038\/sj.onc.1207335","article-title":"Intragenic deletion of CDH1 as the inactivating mechanism of the wild-type allele in an HDGC tumour","volume":"23","author":"Oliveira","year":"2004","journal-title":"Oncogene."},{"key":"2025081901162604500_ref9","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.1053\/j.gastro.2009.02.065","article-title":"Quantification of epigenetic and genetic 2nd hits in CDH1 during hereditary diffuse gastric cancer syndrome progression","volume":"136","author":"Oliveira","year":"2009","journal-title":"Gastroenterology."},{"key":"2025081901162604500_ref10","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1002\/path.2426","article-title":"Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer","volume":"216","author":"Barber","year":"2008","journal-title":"J Pathol"},{"key":"2025081901162604500_ref11","doi-asserted-by":"publisher","DOI":"10.3389\/fmolb.2021.689139","article-title":"Overview on the role of E-cadherin in gastric cancer: dysregulation and clinical implications","volume":"8","author":"Zhao","year":"2021","journal-title":"Front Mol Biosci"},{"key":"2025081901162604500_ref12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s13046-023-02622-3","article-title":"Current advances in understanding the molecular profile of hereditary diffuse gastric cancer and its clinical implications","volume":"42","author":"Lim","year":"2023","journal-title":"J Exp Clin Cancer Res"},{"key":"2025081901162604500_ref13","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1002\/path.1564","article-title":"Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening","volume":"203","author":"Carneiro","year":"2004","journal-title":"J Pathol"},{"key":"2025081901162604500_ref14","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/35101031","article-title":"Two genetic hits (more or less) to cancer","volume":"1","author":"Knudson","year":"2001","journal-title":"Nat Rev Cancer"},{"key":"2025081901162604500_ref15","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1002\/humu.10068","article-title":"Screening E-cadherin in gastric cancer families reveals germline mutations only in hereditary diffuse gastric cancer kindred","volume":"19","author":"Oliveira","year":"2002","journal-title":"Hum Mutat"},{"key":"2025081901162604500_ref16","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1186\/1897-4287-5-4-183","article-title":"A short guide to hereditary diffuse gastric cancer","volume":"5","author":"Guilford","year":"2007","journal-title":"Hered Cancer Clin Pract"},{"key":"2025081901162604500_ref17","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/79120","article-title":"Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer","volume":"26","author":"Grady","year":"2000","journal-title":"Nat Genet"},{"key":"2025081901162604500_ref18","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1038\/sj.emboj.7600136","article-title":"E-cadherin-mediated adhesion inhibits ligand-dependent activation of diverse receptor tyrosine kinases","volume":"23","author":"Qian","year":"2004","journal-title":"EMBO J"},{"key":"2025081901162604500_ref19","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1002\/path.6277","article-title":"Cell division-dependent dissemination following E-cadherin loss underlies initiation of diffuse-type gastric cancer","volume":"263","author":"Monster","year":"2024","journal-title":"J Pathol"},{"key":"2025081901162604500_ref20","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1172\/JCI69738","article-title":"New and emerging HDAC inhibitors for cancer treatment","volume":"124","author":"West","year":"2014","journal-title":"J Clin Invest"},{"key":"2025081901162604500_ref21","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.molonc.2012.09.003","article-title":"HDAC inhibitor-based therapies: can we interpret the code?","volume":"6","author":"New","year":"2012","journal-title":"Mol Oncol"},{"key":"2025081901162604500_ref22","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1038\/s41388-023-02599-5","article-title":"E-cadherin is a biomarker for ferroptosis sensitivity in diffuse gastric cancer","volume":"42","author":"Minikes","year":"2023","journal-title":"Oncogene."},{"key":"2025081901162604500_ref23","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1007\/s10120-021-01191-8","article-title":"Indolent feature of helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations","volume":"24","author":"Nikaido","year":"2021","journal-title":"Gastric Cancer"},{"key":"2025081901162604500_ref24","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1136\/jmg.2009.074237","article-title":"Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research","volume":"47","author":"Fitzgerald","year":"2010","journal-title":"J Med Genet"},{"key":"2025081901162604500_ref25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s10120-009-0531-x","article-title":"Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice","volume":"13","author":"Guilford","year":"2010","journal-title":"Gastric Cancer"},{"key":"2025081901162604500_ref26","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1001\/jamaoncol.2014.168","article-title":"Hereditary diffuse gastric cancer syndrome: CDH1 mutations and beyond","volume":"1","author":"Hansford","year":"2015","journal-title":"JAMA Oncol"},{"key":"2025081901162604500_ref27","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.00640","article-title":"Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast","volume-title":"J Clin Oncol","author":"Yadav"},{"key":"2025081901162604500_ref28","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1136\/jmedgenet-2018-105337","article-title":"Hereditary lobular breast cancer with an emphasis on E-cadherin genetic defect","volume":"55","author":"Corso","year":"2018","journal-title":"J Med Genet"},{"key":"2025081901162604500_ref29","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1054\/bjoc.1999.0965","article-title":"Lobular carcinoma in situ of the breast is not caused by constitutional mutations in the E-cadherin gene","volume":"82","author":"Rahman","year":"2000","journal-title":"Br J Cancer"},{"key":"2025081901162604500_ref30","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1136\/jmg.2007.051268","article-title":"Germline E-cadherin mutations in familial lobular breast cancer","volume":"44","author":"Masciari","year":"2007","journal-title":"J Med Genet"},{"key":"2025081901162604500_ref31","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1053\/j.gastro.2015.06.003","article-title":"Accuracy of hereditary diffuse gastric cancer testing criteria and outcomes in patients with a germline mutation in CDH1","volume":"149","author":"Post","year":"2015","journal-title":"Gastroenterology."},{"key":"2025081901162604500_ref32","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1007\/s10120-019-00945-9","article-title":"Frequency of CDH1 germline variants and contribution of dietary habits in early age onset gastric cancer patients in Brazil","volume":"22","author":"Guindalini","year":"2019","journal-title":"Gastric Cancer"},{"key":"2025081901162604500_ref33","doi-asserted-by":"crossref","first-page":"1598","DOI":"10.3390\/cancers12061598","article-title":"Hereditary gastric and breast cancer syndromes related to CDH1 germline mutation: a multidisciplinary clinical review","volume":"12","author":"Corso","year":"2020","journal-title":"Cancers (Basel)"},{"key":"2025081901162604500_ref34","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1016\/j.ejso.2007.03.001","article-title":"Characterization of the P373L E-cadherin germline missense mutation and implication for clinical management","volume":"33","author":"Corso","year":"2007","journal-title":"Eur J Surg Oncol"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/34\/16\/1345\/63454435\/ddaf092.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/34\/16\/1345\/63454435\/ddaf092.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T05:16:39Z","timestamp":1755580599000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/34\/16\/1345\/8158504"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,9]]},"references-count":34,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2025,6,9]]},"published-print":{"date-parts":[[2025,8,16]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddaf092","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,8,15]]},"published":{"date-parts":[[2025,6,9]]}}}