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. 2004 Sep 23:4:22.
doi: 10.1186/1471-230X-4-22.

Cyclin A and cyclin D1 as significant prognostic markers in colorectal cancer patients

Abeer A Bahnassy  1 , Abdel-Rahman N Zekri, Soumaya El-Houssini, Amal M R El-Shehaby, Moustafa Raafat Mahmoud, Samira Abdallah, Mostafa El-Serafi
Affiliations

Cyclin A and cyclin D1 as significant prognostic markers in colorectal cancer patients

Abeer A Bahnassy et al. BMC Gastroenterol. .

Abstract

Background: Colorectal cancer is a common cancer all over the world. Aberrations in the cell cycle checkpoints have been shown to be of prognostic significance in colorectal cancer.

Methods: The expression of cyclin D1, cyclin A, histone H3 and Ki-67 was examined in 60 colorectal cancer cases for co-regulation and impact on overall survival using immunohistochemistry, southern blot and in situ hybridization techniques. Immunoreactivity was evaluated semi quantitatively by determining the staining index of the studied proteins.

Results: There was a significant correlation between cyclin D1 gene amplification and protein overexpression (concordance = 63.6%) and between Ki-67 and the other studied proteins. The staining index for Ki-67, cyclin A and D1 was higher in large, poorly differentiated tumors. The staining index of cyclin D1 was significantly higher in cases with deeply invasive tumors and nodal metastasis. Overexpression of cyclin A and D1 and amplification of cyclin D1 were associated with reduced overall survival. Multivariate analysis shows that cyclin D1 and A are two independent prognostic factors in colorectal cancer patients.

Conclusions: Loss of cell cycle checkpoints control is common in colorectal cancer. Cyclin A and D1 are superior independent indicators of poor prognosis in colorectal cancer patients. Therefore, they may help in predicting the clinical outcome of those patients on an individual basis and could be considered important therapeutic targets.

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Figures

Figure 1
Figure 1
Normal colonic mucosa showing positive nuclear immunostaining for: (a) cyclin D1, (b) ISH of histone H3 mRNA, (c) Ki-67 and (d) cyclin A
Figure 2
Figure 2
A case of well differentiated adenocarcinoma with positive immunostaining for: (a) cyclin D1, (b) histone H3 mRNA, (c) Ki-67, and (d) cyclin A. Another case of moderately differentiated denocarcinoma with positive immunostaining for: (e) cyclin D1, (f) histone H3 mRNA, (g) Ki-67, and (h) cyclin A. A case of poorly differentiated adenocarcinoma with diffuse staining for: (i) cyclin D1, (j) ISH of histone H3 mRNA, (k) Ki-67 and (l) cyclin A.
Figure 3
Figure 3
A: Southern blot analysis of normal mucosa (N) and their seven corresponding cases of colonic adenocarcinomas (T1–T7), cases No. 1, 2, 4, and 5 are poorly differentiated whereas cases No. 3, 6, and 7 are moderately differentiated. Genomic DNA was digested with BglII, fractionated by electrophoresis in agarose gel, transferred onto membranes and hybridized with PRAD1 and β-actin. Tumors number 1–6 (Lanes 1–6) show different degrees of PRAD1/cyclin D1 amplification, tumor number 7 (lane 7) was not amplified. B: Southern blot analysis of 3 cases of adenocarcinomas (T) and matched normal colonic mucosa (N). Genomic DNA was digested with EcoRI, fractionated by electrophoresis in agarose gel, transferred onto membranes and hybridized with PRAD1 and β-actin probes for loading control. The identification of the 3 tumors is the same as in Fig. 3A with amplification of PRAD1/cyclin D1 in tumors number 4, 5 (Lanes 1, 2) but not 7 (Lane 3).
Figure 4
Figure 4
Correlation between the staining intensity of (a) Ki-67 vs. cyclin D1, (b) Ki-67 vs. histone H3, (c) Ki-67 vs. cyclin A and (d) cyclin A vs. histone H3 mRNA expression.
Figure 5
Figure 5
Kaplan-Meier survival curves for colorectal carcinoma. Overall survival is significantly lower in patients with (a) cyclin A and (b) cyclin D1 overexpression. Patients with high SI for histone H3 mRNA have poorer prognosis but this was not statistically significant (c). No significant difference was present between patients with high Ki-67 SI and those with low Ki-67 SI (d).
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