Early HER2 dysregulation in gastric and oesophageal carcinogenesis

Aims: 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 Barretts adenocarcinoma (BAc). Methods and results: A consecutive series of 275 samples of stomach and oesophagus tissue (representing the whole spectrum of the phenotypic changes involved in gastric and Barretts 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/4B5consistency 97.8%, k = 0.89, P < 0.001; SISH/CB11consistency 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 Barretts oncogenesis.