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. 2006 Jun;8(6):458-64.
doi: 10.1593/neo.06247.

Combined analysis of COX-2 and p53 expressions reveals synergistic inverse correlations with microsatellite instability and CpG island methylator phenotype in colorectal cancer

Shuji Ogino  1 , Mohan Brahmandam, Takako Kawasaki, Gregory J Kirkner, Massimo Loda, Charles S Fuchs
Affiliations

Combined analysis of COX-2 and p53 expressions reveals synergistic inverse correlations with microsatellite instability and CpG island methylator phenotype in colorectal cancer

Shuji Ogino et al. Neoplasia. 2006 Jun.

Abstract

Cyclooxygenase-2 (COX-2) overexpression and mutations of p53 (a known COX-2 regulator) are inversely associated with microsatellite instability-high (MSI-H) and CpG island methylator phenotype (CIMP) characterized by extensive promoter methylation, is associated with MSI-H. However, no studies have comprehensively examined interrelations between COX-2, p53, MSI, and CIMP. Using MethyLight, we measured DNA methylation in five CIMP-specific gene promoters [CACNA1G, CDKN2A (p16/INK4A), CRABP1, MLH1, and NEUROG1] in relatively unbiased samples of 751 colorectal cancer cases obtained from two large prospective cohorts; 115 (15%) tumors were CIMP-high (> or = 4 of 5 methylated promoters), 251 (33%) were CIMP-low (1 to 3 methylated promoters), and the remaining 385 (51%) were CIMP-0 (no methylated promoters). CIMP-high tumors were much less frequent in COX-2+/p53+ tumors (4.6%) than in COX-2+/p53- tumors (19%; P < .0001), COX-2-/p53+ tumors (17%; P = .04), and COX-2-/p53- tumors (28%; P < .0001). In addition, COX-2+/p53+ tumors were significantly less common in MSI-H CIMP-high tumors (9.7%) than in non-MSI-H CIMP-low/CIMP-0 tumors (44-47%; P < .0001). In conclusion, COX-2 and p53 alterations were synergistically inversely correlated with both MSI-H and CIMP-high. Our data suggest that a combined analysis of COX-2 and p53 may be more useful for the molecular classification of colorectal cancer than either COX-2 or p53 analysis alone.

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Figures

Figure 1
Figure 1
COX-2 immunohistochemistry in colorectal cancer. (A) No COX-2 overexpression (negative) in carcinoma (bottom, solid arrows) relative to normal mucosa (top, empty arrow). (B) Weak (1+) overexpression in carcinoma (bottom, solid arrows) relative to normal mucosa (top, empty arrow). (C) Strong (2+) overexpression in carcinoma (top right, solid arrows; normal mucosa at bottom left, empty arrow). (D) Strong (2+) overexpression in carcinoma (top right, solid arrows; normal mucosa at bottom left, empty arrow).
Figure 2
Figure 2
Frequencies of COX-2+/p53+ tumors in the six MSI/CIMP subtypes of colorectal cancer.
Figure 3
Figure 3
Frequencies of COX-2-/p53- tumors in the six MSI/CIMP subtypes of colorectal cancer.
See this image and copyright information in PMC

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