Combined analysis of biomarkers of proliferation and apoptosis in colon cancer: an immunohistochemistry-based study using tissue microarray.

BACKGROUND: Disturbance of the balance between proliferation and apoptosis is an important hallmark of tumor development. The goal of this study was to develop a descriptive parameter that represents this imbalance and relate this parameter to clinical outcome in all four stages of colon cancer.
MATERIAL AND METHODS: The study population consisted of 285 stage I-IV colon cancer patients of which a tumor tissue microarray (TMA) was available. TMA sections were immunohistochemically stained and quantified for the presence of Ki67 and cleaved caspase-3 tumor expression. These results were used to develop the combined apoptosis proliferation (CAP) parameter and correlated to patient outcome.
RESULTS: The CAP parameter was significantly related to clinical outcome; patients with CAP ++ (high level of both apoptosis and proliferation) showed the best outcome perspectives (overall survival (OS), p = 0.004 and disease-free survival (DFS), p = 0.009). The effect of the CAP parameter was related to tumor microsatellite status and indirectly to tumor location, where left-sided tumors with CAP + - (high level of proliferation, low level of apoptosis) showed a worse prognosis (DFS p value 0.02) and right-sided tumors with CAP + - had a better prognosis (DFS p value 0.032). With stratified analyses, the CAP parameter remained significant in stage II tumors only.
CONCLUSIONS: The CAP parameter, representing outcome of the balance between the level of apoptosis and proliferation, can be used as a prognostic marker in colon cancer patients for both DFS and OS, particularly in left-sided, microsatellite stable tumors when tumor-node-metastasis (TNM) stage is taken into account.