ORIGINAL ARTICLE

Decreased xanthine oxidoreductase is a predictor of poor prognosis in early-stage gastric cancer

N Linder¹, C Haglund², M Lundin³, S Nordling⁵, A Ristimäki⁴, A Kokkola², J Mrena², J-P Wiksten³ and J Lundin³

¹ Developmental and Reproductive Biology and Hospital for Children and Adolescents, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland
² Department of Surgery, Helsinki University Central Hospital, Helsinki
³ Department of Oncology, Helsinki University Central Hospital
⁴ Molecular and Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki
⁵ Department of Pathology, University of Helsinki

Correspondence to:
Correspondence to:
N Linder
Research Program for Developmental and Reproductive Biology, Room B524b, Biomedicum Helsinki, University of Helsinki, PO Box 63 (Haartmaninkatu 8), 00014 Helsinki, Finland; nina.linder{at}hus.fi

Background: Xanthine oxidoreductase (XOR) is a key enzyme in the degradation of DNA, RNA and high-energy phosphates. About half of the patients with breast cancer have a decrease in XOR expression. Patients with breast cancer with unfavourable prognosis are independently identified by the loss of XOR.

Aim: To assess the clinical relevance of XOR expression in gastric cancer.

Methods: XOR levels were studied by immunohistochemistry in tissue microarray specimens of 337 patients with gastric cancer and the relation between XOR expression and a series of clinicopathological variables, as well as disease-specific survival, was assessed.

Results: XOR was moderately decreased in 41% and was undetectable in another 14% of the tumours compared with the corresponding normal tissue. Decreased XOR was associated with advanced stage, deep tumour penetration, diffusely spread tumour location, positive lymph node status, large tumour size, non-curative disease, cellular aneuploidy, high S-phase fraction and high cyclooxygenase-2 expression, but not with p53 expression or Borrmann classification. Down regulation of XOR was associated with unfavourable outcome, and the cumulative 5-year gastric cancer-specific survival in patients with strong XOR expression was 47%, compared with 22% in those with moderate to negative expression (p<0.001). This was also true in patients with stage I–II (p = 0.01) and lymph node-negative (p = 0.02) disease, as well as in patients with smaller (5 cm) tumours (p = 0.02).

Conclusion: XOR expression in gastric cancer may be a new marker for a more aggressive gastric cancer biology, similar to that previously reported for breast cancer.

Abbreviations: COX-2, cyclooxygenase-2; SPF, S-phase fraction; XOR, xanthine oxidoreductase

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