Combined analysis of COX-2 and p53 expressions reveals synergistic inverse correlations with microsatellite instability and CpG island methylator phenotype in colorectal cancer.
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.
Ogino
Shuji
S
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA. shuji-ogino@dfci.harvard.edu
Brahmandam
Mohan
M
Kawasaki
Takako
T
Kirkner
Gregory J
GJ
Loda
Massimo
M
Fuchs
Charles S
CS
D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism*; D018899:CpG Islands; D051546:Cyclooxygenase 2 / Q000096:biosynthesis*; D019175:DNA Methylation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D010641:Phenotype; D011446:Prospective Studies; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D016159:Tumor Suppressor Protein p53; D051546:Cyclooxygenase 2