{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T18:04:30Z","timestamp":1762625070156,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T00:00:00Z","timestamp":1693267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e Tecnologia","doi-asserted-by":"publisher","award":["SFRH\/BD\/138670\/2018","NORTE-01-0145-FEDER-072678"],"award-info":[{"award-number":["SFRH\/BD\/138670\/2018","NORTE-01-0145-FEDER-072678"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)","award":["SFRH\/BD\/138670\/2018","NORTE-01-0145-FEDER-072678"],"award-info":[{"award-number":["SFRH\/BD\/138670\/2018","NORTE-01-0145-FEDER-072678"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>The most well-characterized hereditary form of gastric cancer is hereditary diffuse gastric cancer (HDGC), an autosomal dominant syndrome characterized by an increased risk of diffuse gastric and lobular breast cancer. HDGC is predominantly caused by germline pathogenic variants in the CDH1 gene, and more rarely in the CTNNA1 gene. Furthermore, the International Gastric Cancer Linkage Consortium (IGCLC) guidelines do not clarify whether or not mixed gastric cancer (with a diffuse component) should be considered in the HDGC genetic testing criteria. We aimed to evaluate the contribution of CTNNA1 and CTNND1 germline variants to HDGC. Additionally, we also intended to compare the frequencies of CDH1 and CTNNA1 (and eventually CTNND1) germline variants between patients with diffuse and mixed gastric carcinomas to evaluate if genetic testing for these genes should or should not be considered in patients with the latter. We analyzed the CDH1 gene in 67 cases affected with early-onset\/familial mixed gastric carcinomas and the CTNNA1 and CTNND1 genes in 208 cases with diffuse or mixed gastric cancer who had tested negative for CDH1 pathogenic germline variants. A deleterious CTNNA1 germline variant was found in 0.7% (1\/141) of diffuse gastric cancer patients meeting the 2020 IGCLC criteria, as compared to the rate of 2.8% of CDH1 deleterious variants found by us in this setting. No deleterious variants were found in CTNND1, but six variants of uncertain significance were identified in this gene. We did not find any pathogenic CDH1, CTNNA1 or CTNND1 variant in index patients with early-onset\/familial mixed gastric cancer, so there is no evidence that supports including this tumor type in the testing criteria for germline variants in these genes. The role of the CTNND1 gene in inherited gastric cancer predisposition is still unclear.<\/jats:p>","DOI":"10.3390\/cancers15174313","type":"journal-article","created":{"date-parts":[[2023,8,29]],"date-time":"2023-08-29T08:51:14Z","timestamp":1693299074000},"page":"4313","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Frequency of CDH1,\u00a0CTNNA1 and CTNND1 Germline Variants in Families with Diffuse and Mixed Gastric Cancer"],"prefix":"10.3390","volume":"15","author":[{"given":"Joana","family":"Guerra","sequence":"first","affiliation":[{"name":"Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"},{"name":"Doctoral Programme in Biomedical Sciences, School Medicine and Biomedical Sciences, University of Porto (ICBAS-UP), 4050-313 Porto, Portugal"}]},{"given":"Carla","family":"Pinto","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"},{"name":"Department of Pathological, Cytological and Thanatological Anatomy, School of Health, Polytechnic Institute of Porto, 4200-072 Porto, Portugal"}]},{"given":"Pedro","family":"Pinto","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"}]},{"given":"Manuela","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"}]},{"given":"Catarina","family":"Santos","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"}]},{"given":"Ana","family":"Peixoto","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8809-4894","authenticated-orcid":false,"given":"Carla","family":"Escudeiro","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"}]},{"given":"Ana","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6706-9497","authenticated-orcid":false,"given":"Miguel","family":"Porto","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"}]},{"given":"In\u00eas","family":"Francisco","sequence":"additional","affiliation":[{"name":"Molecular Pathobiology Research Unit, Portuguese Oncology Institute of Lisbon, 1099-023 Lisbon, Portugal"}]},{"given":"Paula","family":"Lopes","sequence":"additional","affiliation":[{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"}]},{"given":"Ana Raquel","family":"Isidoro","sequence":"additional","affiliation":[{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"}]},{"given":"Ana Lu\u00edsa","family":"Cunha","sequence":"additional","affiliation":[{"name":"Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"}]},{"given":"Cristina","family":"Albuquerque","sequence":"additional","affiliation":[{"name":"Molecular Pathobiology Research Unit, Portuguese Oncology Institute of Lisbon, 1099-023 Lisbon, Portugal"}]},{"given":"Isabel","family":"Claro","sequence":"additional","affiliation":[{"name":"Gastroenterology Department, Portuguese Oncology Institute of Lisbon, 1099-023 Lisbon, Portugal"},{"name":"Familiar Cancer Risk Clinic, Portuguese Oncology Institute of Lisbon, 1099-023 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8340-2264","authenticated-orcid":false,"given":"Carla","family":"Oliveira","sequence":"additional","affiliation":[{"name":"i3S-Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, 4200-135 Porto, Portugal"},{"name":"IPATIMUP-Instituto de Patologia e Imunologia Molecular da Universidade do Porto, 4200-135 Porto, Portugal"},{"name":"FMUP-Faculty of Medicine of the University of Porto, 4100-179 Porto, Portugal"}]},{"given":"Jo\u00e3o","family":"Silva","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"},{"name":"Medical Genetics Department, Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4896-5982","authenticated-orcid":false,"given":"Manuel R.","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Cancer Genetics Group, IPO-Porto Research Center (CI-IPOP)\/RISE@CI-IPOP (Health Research Network), Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"},{"name":"Department of Laboratory Genetics, Portuguese Oncology Institute of Porto (IPO-Porto)\/Porto Comprehensive Cancer Center, 4200-072 Porto, Portugal"},{"name":"School of Medicine and Biomedical Sciences (ICBAS), University of Porto, 4050-313 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"101800","DOI":"10.1016\/j.bpg.2022.101800","article-title":"Familial and hereditary gastric cancer, an overview","volume":"58\u201359","author":"Carneiro","year":"2022","journal-title":"Best Pract. 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