{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:19:13Z","timestamp":1790849953369,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["PI24\/00737"],"award-info":[{"award-number":["PI24\/00737"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","award":["PI21\/00333"],"award-info":[{"award-number":["PI21\/00333"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Gastric cancer (GC) remains a leading cause of cancer mortality worldwide. While most cases are sporadic, approximately 10% show familial clustering with only a minority explained by known hereditary syndromes. The remaining, termed familial non-hereditary gastric cancer (FNHGC), lack a defined high-penetrance germline mutation. This review aims to summarize current knowledge regarding the diagnosis, risk factors, molecular characteristics and management of FNHGC. Methods: A comprehensive narrative review of the literature was conducted focusing on epidemiologic, molecular and clinical studies addressing families with multiple GC cases but no identified germline mutation. Results: The etiology of FNHGC is multifactorial, and H. pylori, with its related chronic gastritis, is probably the key driver. Familial clustering likely occurs when combined with other elements such as genetic polymorphisms, shared exposures to risk factors or even epigenetic phenomena. Molecular profiling reveals distinct patterns in familial tumors such as more frequent microsatellite instability; somatic CDH1 promoter hypermethylation; and recurrent somatic mutations in TP53, RHOA and DNA repair genes. Current management focuses on genetic testing to rule out hereditary syndromes, endoscopic surveillance and mitigation of risk factors, with eradication of H. pylori paramount. Conclusions: FNHGC represents a distinct subgroup of GC characterized by a multifactorial etiology related to exposure to risk factors and genetic susceptibility although significant gaps remain in fully explaining the condition. Ongoing research holds promise to provide tools for better detection and prevention in order to reduce the burden of GC in familial settings.<\/jats:p>","DOI":"10.3390\/cancers17193209","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T11:06:02Z","timestamp":1759316762000},"page":"3209","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Familial Non-Hereditary Gastric Cancer: Diagnosis, Management, Molecular Characteristics and Future Perspective"],"prefix":"10.3390","volume":"17","author":[{"given":"Carlos","family":"Pardo","sequence":"first","affiliation":[{"name":"Servei de Gastroenterologia, Hospital Cl\u00ednic de Barcelona, Universitat de Barcelona (UB), c. Villarroel, 170, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Luzko","sequence":"additional","affiliation":[{"name":"Servei de Gastroenterologia, Hospital Cl\u00ednic de Barcelona, Universitat de Barcelona (UB), c. Villarroel, 170, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona (UB), c. Casanova, 143, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0639-1906","authenticated-orcid":false,"given":"Joaqu\u00edn","family":"Castillo-Iturra","sequence":"additional","affiliation":[{"name":"Servei de Gastroenterologia, Hospital Cl\u00ednic de Barcelona, Universitat de Barcelona (UB), c. Villarroel, 170, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona (UB), c. Casanova, 143, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9726-5712","authenticated-orcid":false,"given":"Elisa","family":"Cant\u00fa-Germano","sequence":"additional","affiliation":[{"name":"Servei de Gastroenterologia, Hospital Cl\u00ednic de Barcelona, Universitat de Barcelona (UB), c. Villarroel, 170, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona (UB), c. Casanova, 143, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4518-8591","authenticated-orcid":false,"given":"Leticia","family":"Moreira","sequence":"additional","affiliation":[{"name":"Servei de Gastroenterologia, Hospital Cl\u00ednic de Barcelona, Universitat de Barcelona (UB), c. Villarroel, 170, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), c. Villarroel, 170, 08036 Barcelona, Spain"},{"name":"Facultat de Medicina i Ci\u00e8ncies de la Salut, Universitat de Barcelona (UB), c. Casanova, 143, 08036 Barcelona, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Hep\u00e1ticas y Digestivas (CIBEREHD), c. Monforte de Lemos, 3-5, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,1]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1111\/apm.1965.64.1.31","article-title":"The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification","volume":"64","author":"Lauren","year":"1965","journal-title":"Acta Pathol. Microbiol. 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