Cyclooxygenase 2 Expression in Colorectal Cancer with DNA Mismatch Repair Deficiency

Abstract

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 to15% 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/MLH1expression 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 MMRdeficient 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.

Protein expression of Fragile Histidine Triad and cyclooxgenase-2 in serrated neoplasia of the colorectum

“…At the same time, P53-positive rates were rare in serrated polyps. P53 overexpression appears to become more frequent as tumors progress to higher grades of neoplasia, in agreement with previous studies (36,37).…”

Cyclooxygenase as a Target for Colorectal Cancer Chemoprevention

“…In a recent study [56], it was confirmed that while most MMR-proficient CRC exhibited COX-2 overexpression, half of those tumors with a deficient repair system did not overexpress this protein. Interestingly, the lack of COX-2 overexpression was observed almost exclusively in patients with MMR-deficient sporadic forms, thus suggesting an epigenetic mechanism responsible for gene silencing.…”

DNA repair systems

“…It is believed that the mechanism of suppression is related to inhibi on of cyclooxygenase-2 (COX2), as it has been found to be overexpressed in many cancers (colorectal cancer, including HNPCC; bladder cancer; oesophageal cancer, and others) [553][554][555]. The prolonged use of specific COX-2 inhibitors has been found to be associated with decreased risk for colorectal cancer [556,557]; but, somewhat paradoxically, with increased risk for breast cancer and haematological cancers [558].…”