title: E-cadherin genetic screening and clinico-pathologic characteristics of early onset gastric cancer.
abstract: OBJECTIVE
  CDH1 germline alterations occur in about 40% of hereditary diffuse gastric cancer (HDGC) families. CDH1 germline mutations are also documented in few early onset diffuse gastric cancer patients (EODGC) without family history, but the real frequency in this setting in unknown. In these patients, the advanced stage at the time of diagnosis remains a clinical burden due to the poor long term survival.
  
  
  METHODS
  The entire coding region and exon flanking sequences of the CDH1 gene was analysed by direct sequencing in 21 EODGC patients aged ≤50 years. The potential deleterious nature for a new CDH1 missense variant was assessed by cell-cell aggregation and invasion assays. Somatic CDH1 mutation, loss of heterozygosity (LOH) and promoter hypermethylation was explored in the tumour from one CDH1 germline mutation carrier.
  
  
  RESULTS
  Two novel CDH1 germline variants were identified in 21 EODGC cases, c.670C>T and -63C>A. Functional analysis of the c.670C>T missense variant classified this mutation as non-pathogenic. The analysis of CDH1 somatic second hits failed to demonstrate E-cadherin structural and epigenetic alterations in the tumour sample.
  
  
  CONCLUSIONS
  Data from the present work and a systematic review of the literature revealed that CDH1 germline mutations occurred in 7.2% of EOGC patients invariably with diffuse of mixed histology. From these, proved CDH1 mutation pathogenicity has been assigned only to 2.3% of the cases who were recurrently diagnosed before 35 years old. Germline CDH1 mutation remain the only germline genetic defect described in this type of patients and CDH1 mutation screening should be recommended for patients with these characteristics.
authors.affiliation: Department of Human Pathology and Oncology, Unit of Surgical Oncology, University of Siena and Istituto Toscano Tumori, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Corso
authors.forename: Corrado
authors.initials: C
authors.lastname: Pedrazzani
authors.forename: Hugo
authors.initials: H
authors.lastname: Pinheiro
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernandes
authors.forename: Daniele
authors.initials: D
authors.lastname: Marrelli
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinnovati
authors.forename: Valeria
authors.initials: V
authors.lastname: Pascale
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.forename: Franco
authors.initials: F
authors.lastname: Roviello
mesh_terms: D000328:Adult; D015703:Antigens, CD; D015820:Cadherins / Q000235:genetics*; D002448:Cell Adhesion; D019175:DNA Methylation / Q000235:genetics; D055088:Early Detection of Cancer; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing / Q000379:methods; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D009361:Neoplasm Invasiveness; D013274:Stomach Neoplasms / Q000175:diagnosis*
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins