Increased cyclooxygenase-2 expression in duodenal compared with colonic tissues in familial adenomatous polyposis and relationship to the -765G -> C COX-2 polymorphism.
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.
Brosens
Lodewijk A A
LA
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Lodewijk.Brosens@student.uva.nl
Iacobuzio-Donahue
Christine A
CA
Keller
Josbert J
JJ
Hustinx
Steven R
SR
Carvalho
Ralph
R
Morsink
Folkert H
FH
Hylind
Linda M
LM
Offerhaus
G Johan
GJ
Giardiello
Francis M
FM
Goggins
Michael
M
D000236:Adenoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D011125:Adenomatous Polyposis Coli / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D000328:Adult; D000368:Aged; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D051546:Cyclooxygenase 2; D004252:DNA Mutational Analysis; D004379:Duodenal Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics* / Q000378:metabolism
D008565:Membrane Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases