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Increased Cyclooxygenase-2 Expression in Duodenal Compared with Colonic Tissues in Familial Adenomatous Polyposis and Relationship to the –765G C COX-2 Polymorphism

Authors' Affiliations: Departments of ¹ Pathology, ² Medicine, and ³ Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland and ⁴ Department of Pathology, Academic Medical Center, Amsterdam, the Netherlands

Requests for reprints: Lodewijk Brosens, Department of Pathology, Academic Medical Center, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands. Phone: 31-20-566-5635; Fax: 31-20-090-0389; E-mail: Lodewijk.Brosens{at}student.uva.nl.

Background: Colorectal cancers arising in patients with familial adenomatous polyposis (FAP) can be largely prevented by polyp surveillance and prophylactic colectomy. As a result, duodenal adenocarcinoma has become a leading cause of death in patients with FAP. Cyclooxygenase 2 (COX-2) inhibition is effective against colorectal polyposis in FAP, but is less effective in treating duodenal polyps. We compared the expression of COX-2 in duodenal and colorectal adenomas from patients with FAP and from patients with sporadic neoplasms and correlated expression to a COX-2 promoter polymorphism (–765G/C) that is reported to influence COX-2 expression.

Methods: The study population included 36 FAP patients with colonic adenomas, 22 FAP patients with duodenal adenomas, 22 patients with sporadic duodenal adenomas, and 17 patients with sporadic duodenal adenocarcinoma. Neoplastic and corresponding normal tissue COX-2 expressions were determined using immunohistochemistry on tissue microarrays. The prevalence and ethnic distribution of a polymorphism in the COX-2 promoter that influences COX-2 expression (–765G C) were determined in DNA from 274 individuals by real-time quantitative PCR.

Results: Among patients with FAP, histologically normal duodenal mucosa showed higher COX-2 expression than normal colonic mucosa (P < 0.02), and duodenal adenomas had higher COX-2 expression than colonic adenomas (P 0.01). In addition, the normal duodenum of patients with FAP showed higher COX-2 expression than the normal duodenal mucosa of patients with sporadic adenomas (P < 0.05). COX-2 expression was significantly higher in the normal-appearing (P < 0.01) mucosa of patients with FAP carrying the –765GG genotype compared with those carrying the –765GC or –765CC genotypes. The –765C genotype was more common in African Americans than in Caucasians (52% versus 33%, P < 0.01).

Conclusions: High COX-2 expression in the normal and adenomatous duodenal mucosa of patients with FAP may explain the poorer response of these neoplasms to chemoprevention with COX-2 inhibitors.

Key Words: Chemoprevention • Colorectal neoplasia • COX-2 • Duodenal adenomas • Familial adenomatous polyposis • Polymorphism • Nonsteroidal anti-inflammatory drugs

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