Implications of low COX-2 expression in colorectal neoplasms with defective DNA mismatch repair.
Most colorectal adenomas and carcinomas arise in the setting of chromosomal instability and progressive loss of heterozygosity. Approximately 15-20% of colorectal neoplasms arise through a distinct genetic pathway characterized by microsatellite instability (MSI) and frequent loss of expression of one of the DNA mismatch repair enzymes, most often hMLH1 or hMSH2. These distinct genetic pathways are reflected by differences in tumor histopathology, distribution in the colon, prognosis, and dwell time required for progression from adenoma to carcinoma. The molecular and clinical distinctions between these tumors suggest that they are biologically distinct and may respond differently to therapeutic and chemopreventive agents. Recently, we showed that expression of a putative chemopreventive target, COX-2, is significantly reduced in colorectal cancers with defective mismatch repair as assessed by MSI and absent staining for hMLH1 and/or hMSH2. The mechanisms responsible for low COX-2 expression in tumors with MSI remain unknown, but they may be linked to molecular events giving rise to MSI tumors. Although the clinical implications of these observations are unknown, the presence of MSI should be considered an important variable when assessing the efficacy of COX-2 inhibitors in chemoprevention trials.
Karnes
W E
WE
Colorectal Neoplasia Group, Mayo Clinic, Rochester, Minnesota 55905, USA. karnes.william@mayo.edu
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D020137:Base Pair Mismatch; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics*; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D004260:DNA Repair; D004268:DNA-Binding Proteins; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D008565:Membrane Proteins; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004268:DNA-Binding Proteins; D007527:Isoenzymes; C501486:MLH1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein