Relationship between Ki-67 and p53 expression and survival in men with colorectal cancer

Background: In patients with colorectal cancer (CRC) several independent prognostic factors are well-supported in the literature, including TNM staging, histologic type and grade, carcinoembryonic antigen (CEA) serum levels, and tissue proliferation markers such as Ki-67 and p53. Ki-67 is a nonhistone nuclear protein that is closely linked to proliferating cells. High Ki-67 expression has been shown to be associated with a higher histologic grade, the presence of lymph nodal metastasis, and shorter disease-free and overall survival in patients with CRC. In addition, a positive correlation between Ki-67 proliferation index and pathologic tumor response to neoadjuvant chemotherapy has been reported, implicating the role of Ki-67 in response to treatment. P53 is a tumor suppressor gene that controls the induction of apoptosis and growth arrest at cell cycle check points. In normal cells, p53 is usually inactive, bounds to the protein MDM2 which prevents its action, and promotes its degradation by acting as ubiquitin ligase. The p53 gene encodes for a 53-kDa nuclear phosphoprotein, which has been implicated in controlling cell-cycle regulation, differentiation, DNA repair, and apoptosis. Unlike normal p53, nonfunctional mutated p53 accumulates in the nucleus of tumor cells, and, therefore, it can be detected by immunohistochemical analysis. The function of p53 leads to elimination of damaged cells from a population and is believed to be a basis of its tumor suppressor function. Patients and Methods: Charts of a homogeneous group of 31 male patients (median age 65 years, range 48-75 years) who underwent curative surgery for Dukes’ B colorectal adenocarcinoma were reviewed, and the following parameter were recorded: age of the patients, baseline CEA serumlevels, Ki-67 and p53 expression, and survival. The Ki-67 and p53 protein immunoreactivity and intensity was semi-quantitatively evaluated in at least 1000 cells examined at 40x magnification and recorded as the percentage of positive tumor cells over the total number of neoplastic cells present in the same area. Immunohistochemical staining was performed using an automated immunostainer. A known positive control section was included in each run to ensure proper staining. Rabbit immunoglobulin fraction (normal) or nonspecific IgG1 monoclonal diluted with phosphate-buffered saline was used as a negative control. Monoclonal antibodies were used for both Ki-67 (MIB-1), and p53 (DO-7). CEA serum levels were determined by automated testing using a two-site enzyme-linked immunosorbent assay. The overall mean preoperative CEA serum level was 7.9±7.5 ng/mL. Results: The mean survival was 37.3±13.7 months. There was a significant inverse relationship between survival and both Ki-67 (R=-67, p=<0.001) and p53 (R=-0.64, p<0.001), and between Ki-67 and p53 (R=0.82, p<0.001). No correlation was found between survival and both age (R=0.22, p=0.22) and CEA (R=0.08, p=0.67), and between CEA, age (R=0.34, p=0.06), Ki-67 (R=-0.021, p=0.90), and p53 (R=0.03, p=0.87). Conclusions: Ki-67 and p53 overexpression in CRC is associated with a worse outcome, and in this selected group of patients these prognostic markers were independent of age, while preoperative CEA serum levels did not show any relationship with survival.