title: Hereditary diffuse gastric cancer - pathophysiology and clinical management.
abstract: Hereditary Diffuse Gastric Cancer is an autosomal dominant inherited gastric cancer syndrome caused by germline alterations in CDH1 (E-cadherin) and CTNNA1 (alpha-E-catenin) genes. Germline CDH1 alterations encompass small frameshifts, splice-site, nonsense, and missense mutations, as well as large rearrangements. Most CDH1 truncating mutations are pathogenic, and several missense CDH1 mutations have a deleterious effect on E-cadherin function. CDH1 testing should be performed in probands. Screening of at-risk individuals is indicated from the age of consent following counselling with a multidisciplinary team. In mutation-positive individuals prophylactic gastrectomy is recommended. Endoscopic surveillance is an option for those refusing/postponing gastrectomy, those with mutations of undetermined significance, and in CDH1-negative families. Ongoing research focus on the search of genetic causes other than CDH1 or CTNNA1 germline defects; assessment of the pathogenicity and penetrance of CDH1 missense mutations and identification of somatic mechanisms behind the progression from early (indolent) lesions to invasive (lethal) carcinomas.
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal.
authors.forename: Hugo
authors.initials: H
authors.lastname: Pinheiro
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal; Dept. of Pathology and Oncology, Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4100-319 Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal; Dept. of Pathology and Oncology, Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4100-319 Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.affiliation: Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup), Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal; Dept. of Pathology and Oncology, Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4100-319 Porto, Portugal; Centro Hospitalar S. João, Alameda Prof. Hernani Monteiro, 4100-319 Porto, Portugal. Electronic address: fcarneiro@ipatimup.pt.
authors.forename: Fátima
authors.initials: F
authors.lastname: Carneiro
mesh_terms: D065311:Adenocarcinoma in Situ / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D013274:Stomach Neoplasms / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D051178:alpha Catenin / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; C495273:CTNNA1 protein, human; D015820:Cadherins; D051178:alpha Catenin
keywords: Alpha-E-catenin; CDH1; CTNNA1; E-cadherin; Familial gastric cancer; Genetic counselling and; Hereditary diffuse gastric cancer; Hereditary gastric cancer; In situ carcinoma; Pagetoid spread; Prophylactic gastrectomy; Surveillance endoscopy; testing