The Mutual Relationship Between P27(CDK1B/KIP1)Regulation, Microsatellite Instability (MSI), CpG Island Methylator Phenotype (CIMP) And The Clinical Features Of Human Sporadic Colorectal Cancer

Background Colorectal cancer (CRC) is one of the most common types of malignant tumors in gastrointestinal system with high incidence and mortality. It has aroused much attention In China. The prognosis of CRC patients depends on early clinical treatment and the early disease evaluation. P27protein is a kind of cyclin dependent kinase inhibitors (CKIs). Over expression of p27protein in mammalian cells induces a G1block of the cell cycle and is accepted as a independent indicator to CRC disease prognosis. Methylation of promoter region CpG islands, which is defined as CpG Island Methylator Phenotype (CIMP) is associated with transcriptional inactivation of tumor-suppressor genes in neoplasia so it is related with the incidence and development of CRC. The form of genomic instability associated with defective DNA mismatch repair in tumors is to be called Microsatellite instability (MSI) and it has close relationship with the tumor location and the patient survival rate.Objective To evaluate the expression of P27expression, CIMP and MSI in CRC tissue, examine the relationship between them and identify their clinical significance.Methods The postoperative tumor tissue samples and their paired normal colorectal tissue from49patients with sporadic CRC were collected from April2004to July2006in our hospital. The clinical pathologic data of these patients were integrated, with the follow-up period of30to60months. Immunohistochemistry was used to examine P27expression, methylation-specific polymerase chain reaction (PCR) was employed to determine the methylation status of the respective CpG island and five microsatellite markers were used to determine MSI by PCR. Clinical significance was evaluated by standard statistical methods.Results Of49patients with sporadic CRC involved in this study, the percentage of P27positive tumors was24%(11of48), which was significantly lower than that of P27positive cases (70%;32of48) in paired normal(p=4.92×10-5)。 One year survival rate in P27positive cancer patients is100%and3years is83%, which is a bit greater than P27negative patient, but with no significant differences. The down regulation of P27in CRC tissues might contribute to the down survival ratio (p=0.476). In additional, no hint of association was found between P27expression, CIMP status and MSI occurrence. No remarkable differences were found in characteristics of MSI occurrence between CRC tissues and normal tissues. No close relationship was found between MSI occurrence and the clinical features. The increase of CIMP high (CIMP-H) status in CRC tissues is only a trend compared with normal tissues, for6of43(14%) CRC tissues were CIMP-H while2of38(5%) normal tissues were CIMP-H. Patients with CIMP-H tumors has lower survival rate than CIMP-L/CIMP-0tumors, p=0.024.Conclusions Lower expression of P27, MSI-H and CIMP-H were found in CRC tissues. The down regulation of P27expression makes no significant contribute to lower survival ratio in CRC patients. No remarkable clinical significance was found in MSI occurrence of CRC tissues. The hint of association was only a hint between CIMP-H and the decrease of survival ratio in CRC. The relationship was not found among low expression of P27, MSI-H and CIMP-H.