Cyclin A and Cyclin D1 as Significant Prognostic Markers in Egyptian Patients with Colorectal Carcinoma

Background: Colon cancer is becoming a common cancer in Egypt. It also has unique characteristics that differ from those reported in the western society. Aberrations in the cell cycle checkpoints are common features of several tumors and many have been shown to be of prognostic significance in colorectal carcinoma. Material and Methods: In the present study, four components of the cell cycle regulator proteins [cyclin D1, cyclin A, histone H3 and the Ki-67] were examined in 60 cases of well-characterized colorectal adenocarcinomas, 47 colon and 13 rectal carcinomas, to ascertain co-regulation and impact on survival. Immunohistochemistry was used to study the expression level of Ki-67, cyclin A and cyclin D1 while Southern blot was used to assess cyclin D1gene status, and in situ hybridization was used to study histone H3 mRNA expression. Immunoreactivity was evaluated semi quantitatively using a scoring system that calculates the staining index (SI). Results: There was a significant correlation between cyclin D1 gene amplification and its protein overexpression (concordance = 63.6%). However, some cases revealed protein overexpression without gene amplification indicating that there should be other mechanisms for aberrant accumulation of the protein. The expression of Ki-67 significantly correlated with the other 3 proteins as well as with cyclin D1 amplification. The SIs for Ki-67, cyclin A and cyclin D1 were higher in large-sized, poorly differentiated tumors. Furthermore, the SIs of Ki-67 and histone H3 were higher in patients > 50 years of age. The SI of cyclin D1 was significantly higher in cases with deeply invasive tumors and those with positive lymph node metastasis. The overall survival was significantly lower in patients whose tumors showed cyclin A overexpression as well as those with cyclin D1 amplification and/or overexpression. Multivariate analysis showed that up-regulation of cyclin D1 and cyclin A were two independent prognostic factors in colorectal carcinoma patients.