title: Hypoxia-inducible factor-1alpha expression in the gastric carcinogenesis sequence and its prognostic role in gastric and gastro-oesophageal adenocarcinomas.
abstract: 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-1alpha expression and prognosis was assessed in resection specimens from 177 patients with gastric and gastro-oesophageal junction adenocarcinoma. Hypoxia-inducible factor-1alpha 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-1alpha, 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-1alpha lost prognostic significance in multivariate analysis. The results suggest HIF-1alpha is involved in gastric carcinogenesis and disease progression, but is only a weak prognostic factor for survival.
authors.affiliation: Academic Radiation Oncology, Division of Cancer Studies, The University of Manchester, Christie Hospital, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: E A
authors.initials: EA
authors.lastname: Griffiths
authors.forename: S A
authors.initials: SA
authors.lastname: Pritchard
authors.forename: H R
authors.initials: HR
authors.lastname: Valentine
authors.forename: N
authors.initials: N
authors.lastname: Whitchelo
authors.forename: P W
authors.initials: PW
authors.lastname: Bishop
authors.forename: M P
authors.initials: MP
authors.lastname: Ebert
authors.forename: P M
authors.initials: PM
authors.lastname: Price
authors.forename: I M
authors.initials: IM
authors.lastname: Welch
authors.forename: C M L
authors.initials: CM
authors.lastname: West
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000378:metabolism* / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D001706:Biopsy; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000601:surgery; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000737:chemistry; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D011237:Predictive Value of Tests; D011379:Prognosis; D013194:Staining and Labeling; D013274:Stomach Neoplasms / Q000175:diagnosis* / Q000378:metabolism* / Q000601:surgery; D015996:Survival Rate
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit