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Cyclooxygenase 2 Expression in Colorectal Cancer with DNA Mismatch Repair Deficiency

Authors' Affiliations: ¹ Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona; ² Department of Gastroenterology, Hospital del Mar, Barcelona, Spain; Departments of ³ Pathology and ⁴ Gastroenterology, Hospital General Universitario de Alicante, Alicante, Spain; ⁵ Cancer Epigenetic Laboratory, Spanish National Cancer Centre, Madrid, Spain; ⁶ Department of Gastroenterology, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; ⁷ Department of Gastroenterology, Hospital Clínico, Zaragoza, Spain; ⁸ Department of Gastroenterology, Hospital General de Vic, Vic, Spain; ⁹ Department of Gastroenterology, Hospital General Universitario, Valencia, Spain; and ¹⁰ Department of Gastroenterology, Hospital Universitario Reina Sofía, Córdoba, Spain

Requests for reprints: Antoni Castells, Department of Gastroenterology, Hospital Clínic, Villarroel 170, 08036 Barcelona, Catalonia, Spain. Phone: 34-93-227-54-18; Fax: 34-93-227-93-87; E-mail: castells{at}clinic.ub.es.

Background: Cyclooxygenase 2 (COX-2) overexpression is a frequent but not universal event in colorectal cancer. It has been suggested that COX-2 protein expression is reduced in colorectal cancer with a defective mismatch repair (MMR) system, a phenomenon commonly associated with hereditary nonpolyposis colorectal cancer (HNPCC) but also present in up to 15% of sporadic tumors.

Aim: To assess COX-2 expression in a large series of fully characterized colorectal cancer patients with respect to the MMR system and to dissect the mechanisms responsible for altered COX-2 expression in this setting.

Patients and Methods: MMR-deficient colorectal cancer were identified in a nationwide, prospective, multicenter study (EPICOLON project). Control MMR-proficient colorectal cancer patients were randomly selected. COX-2 expression was evaluated by immunohistochemistry. Personal and familial characteristics, as well as MSH2/MLH1 expression and germ line mutations, were evaluated.

Results: One hundred fifty-three patients, 46 with MMR deficiency and 107 with MMR proficiency, were included in the analysis. Overall, tumor COX-2 overexpression was observed in 107 patients (70%). COX-2 overexpression was observed in 85 patients (79%) with a MMR-proficient system, but only in 22 patients (48%) with a MMR-deficient colorectal cancer (P < 0.001). The lack of COX-2 overexpression was independently associated with a MMR-deficient system (odds ratio, 3.89; 95% confidence interval, 1.78-8.51; P = 0.001) and a poor degree of differentiation (OR, 3.83; 95% CI, 1.30-11.31; P = 0.015). In the subset of patients with a MMR-deficient colorectal cancer, lack of COX-2 overexpression correlated with a poor degree of differentiation, no fulfillment of Amsterdam II criteria, absence of MSH2/MLH1 germ line mutations, presence of tumor MSH2 expression, and lack of tumor MLH1 expression. CpG island promoter hypermethylation of COX2 was observed in 6 of 18 (33%) tumors lacking COX-2 expression in comparison with 2 of 28 (7%) tumors expressing this protein (P = 0.04).

Conclusions: Up to half of MMR-deficient colorectal cancer do not show COX-2 overexpression, a fact observed almost exclusively in patients with sporadic forms. COX2 hypermethylation seems to be responsible for gene silencing in one third of them. These results suggest the potential utility of nonsteroidal anti-inflammatory drugs in HNPCC chemoprevention and may explain the lack of response of this approach in some sporadic tumors.