title: Early HER2 dysregulation in gastric and oesophageal carcinogenesis.
abstract: OBJECTIVE
  To explore human epidermal growth factor receptor 2 (HER2) status in the histological phenotypes [metaplasia, intraepithelial neoplasia (IEN, i.e. dysplasia), and adenocarcinoma] involved in the morphogenesis of both intestinal-type gastric cancer (GC) and Barrett's adenocarcinoma (BAc).
  
  
  RESULTS
  A consecutive series of 275 samples of stomach and oesophagus tissue (representing the whole spectrum of the phenotypic changes involved in gastric and Barrett's carcinogenesis) was studied. HER2 status was assessed by applying two immunohistochemistry (IHC) protocols, using the antibodies 4B5 and CB11. Dual-colour silver chromogenic in-situ hybridization (SISH) was also performed on the same tissue samples. In both oesophageal and gastric samples, the rate of HER2 overexpression rose significantly from low-grade to high-grade IEN to adenocarcinoma (P < 0.001), with the two IHC protocols showing consistent staining (consistency 95%; k = 0.78; P < 0.001). Intratumour heterogeneity was documented in both GC and BAc (using both IHC protocols). The rate of HER2 amplification (using SISH) increased significantly along with IEN dedifferentiation (P < 0.001). Neither native nor metaplastic mucosa samples (obtained from either stomach or oesophagus) ever showed HER2 amplification. There was excellent agreement between HER2 amplification and protein overexpression (both IHC protocols: SISH/4B5--consistency 97.8%, k = 0.89, P < 0.001; SISH/CB11-consistency 97.8%, k = 0.91, P < 0.001).
  
  
  CONCLUSIONS
  There is early involvement of HER2 dysregulation (amplification and protein overexpression) in both gastric (intestinal-type) and Barrett's oncogenesis.
authors.affiliation: Surgical Pathology & Cytopathology Unit, Department of Medicine, University of Padua, Padua, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Fassan
authors.forename: Luca
authors.initials: L
authors.lastname: Mastracci
authors.forename: Federica
authors.initials: F
authors.lastname: Grillo
authors.forename: Vittorina
authors.initials: V
authors.lastname: Zagonel
authors.forename: Sara
authors.initials: S
authors.lastname: Bruno
authors.forename: Giorgio
authors.initials: G
authors.lastname: Battaglia
authors.forename: Francesca
authors.initials: F
authors.lastname: Pitto
authors.forename: Donato
authors.initials: D
authors.lastname: Nitti
authors.forename: Tiziana
authors.initials: T
authors.lastname: Celiento
authors.forename: Giovanni
authors.initials: G
authors.lastname: Zaninotto
authors.forename: Roberto
authors.initials: R
authors.lastname: Fiocca
authors.forename: Massimo
authors.initials: M
authors.lastname: Rugge
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001471:Barrett Esophagus / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002278:Carcinoma in Situ / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004938:Esophageal Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D018734:Genes, erbB-2; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008679:Metaplasia; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human