Hypoxia-inducible factor-1α expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas

Hypoxia-inducible factor-1 (HIF-1)alpha expression was studied in the gastric carcinogenesis sequence and as a prognostic factor in surgically resected gastric and gastro-oesophageal junction tumours. Protein expression was examined using immunohistochemistry on formalin-fixed biopsies of normal mucosa (n = 20), Helicobacter pylori associated gastritis ( n 24), intestinal metaplasia ( n 24), dysplasia ( n 12) and intestinal ( n 19) and diffuse ( n 21) adenocarcinoma. The relationship between HIF-1 alpha expression and prognosis was assessed in resection specimens from 177 patients with gastric and gastro-oesophageal junction adenocarcinoma. Hypoxia-inducible factor-1 alpha expression was not observed in normal gastric mucosa but increased in density (P < 0.01) and intensity (P < 0.01) with progression from H. pylori- associated gastritis, intestinal metaplasia, dysplasia to adenocarcinoma. The pattern of staining in the resection specimens was focally positive in 49 (28%) and at the invasive tumour edge in 41 (23%). Invasive edge expression was associated with lymph node metastases (P = 0.034), advanced TNM stage (P = 0.001) and was an adverse prognostic factor for cancer-specific survival (P = 0.019). In univariate analysis and in comparison with tumours not expressing HIF-1 alpha, invasive edge staining was associated with a hazard ratio of 1.6 ( 95% CI 1.0 - 2.5) and focally positive staining a hazard ratio of 0.7 ( 95% CI 0.5 - 1.2). Hypoxia-inducible factor-1 alpha lost prognostic significance in multivariate analysis. The results suggest HIF-1 alpha is involved in gastric carcinogenesis and disease progression, but is only a weak prognostic factor for survival.