Title | Combined analysis of COX-2 and p53 expressions reveals synergistic inverse correlations with microsatellite instability and CpG island methylator phenotype in colorectal cancer. |
Publication Type | Journal Article |
Year of Publication | 2006 |
Authors | Ogino S, Brahmandam M, Kawasaki T, Kirkner GJ, Loda M, Fuchs CS |
Journal | Neoplasia |
Volume | 8 |
Issue | 6 |
Pagination | 458-64 |
Date Published | 2006 Jun |
ISSN | 1476-5586 |
Keywords | Cohort Studies, Colorectal Neoplasms, CpG Islands, Cyclooxygenase 2, DNA Methylation, Female, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Genes, p53, Humans, Male, Microsatellite Repeats, Phenotype, Prospective Studies, Tumor Suppressor Protein p53 |
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. |
DOI | 10.1593/neo.06247 |
Alternate Journal | Neoplasia |
PubMed ID | 16820091 |
PubMed Central ID | PMC1601473 |
Grant List | P01 CA055075 / CA / NCI NIH HHS / United States P01 CA087969 / CA / NCI NIH HHS / United States P01 CA55075-13 / CA / NCI NIH HHS / United States P01 CA87969-03 / CA / NCI NIH HHS / United States |
Related Faculty:
Massimo Loda, M.D.