title: Hypoxia-associated markers in gastric carcinogenesis and HIF-2alpha in gastric and gastro-oesophageal cancer prognosis.
abstract: The study investigated hypoxia-associated markers (HIF-2alpha, Epo, Epo-R, Glut-1 and VEGF) along with Ki-67 in a gastric carcinogenesis model, and the prognostic significance of hypoxia-inducible factor (HIF)-2alpha in surgically treated gastro-oesophageal cancer. Protein expression was examined using immunohistochemistry on formalin-fixed, paraffin-embedded 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. Relationships between HIF-2alpha expression and prognosis were assessed in resection specimens from 177 patients with gastric and gastro-oesophageal junction adenocarcinoma. Expression of all markers increased with progression along the gastric carcinogenesis sequence (P=0.0001). Hypoxia-inducible factor-2alpha was expressed in 63% of 177 resection specimens and at a high level in 44%. The median overall survival in patients with HIF-2alpha-expressing tumours was 22 (95% CI 18-26) months, whereas those with HIF-2alpha-negative tumours had a median survival of 37 (95% CI 29-44) months (P=0.015). Hypoxia-inducible factor-2alpha had no independent prognostic significance in multivariate analysis. In view of the lack of independent prognostic significance, HIF-2alpha has no role as a routine prognostic indicator. However, the high expression of HIF-2alpha suggests that it may be of value as a potential therapeutic target.
authors.affiliation: Academic Department of Radiation Oncology, School of Cancer & Imaging Sciences, The University of Manchester, Christie Hospital, Wilmslow Road, Withington, 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: S M
authors.initials: SM
authors.lastname: McGrath
authors.forename: H R
authors.initials: HR
authors.lastname: Valentine
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: D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis*; D015415:Biomarkers; D004938:Esophageal Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D005260:Female; D051272:Glucose Transporter Type 1 / Q000032:analysis; D006801:Humans; D000860:Hypoxia / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human