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. 2012 Jan 3;106(1):133-40.
doi: 10.1038/bjc.2011.504. Epub 2011 Nov 22.

Specific activity of cyclin-dependent kinase I is a new potential predictor of tumour recurrence in stage II colon cancer

E C M Zeestraten  1 , M Maak, M Shibayama, T Schuster, U Nitsche, T Matsushima, S Nakayama, K Gohda, H Friess, C J H van de Velde, H Ishihara, R Rosenberg, P J K Kuppen, K-P Janssen
Affiliations

Specific activity of cyclin-dependent kinase I is a new potential predictor of tumour recurrence in stage II colon cancer

E C M Zeestraten et al. Br J Cancer. .

Erratum in

  • Br J Cancer. 2012 Feb 14;106(4):792

Abstract

Background: There are no established biomarkers to identify tumour recurrence in stage II colon cancer. As shown previously, the enzymatic activity of the cyclin-dependent kinases 1 and 2 (CDK1 and CDK2) predicts outcome in breast cancer. Therefore, we investigated whether CDK activity identifies tumour recurrence in colon cancer.

Methods: In all, 254 patients with completely resected (R0) UICC stage II colon cancer were analysed retrospectively from two independent cohorts from Munich (Germany) and Leiden (Netherlands). None of the patients received adjuvant treatment. Development of distant metastasis was observed in 27 patients (median follow-up: 86 months). Protein expression and activity of CDKs were measured on fresh-frozen tumour samples.

Results: Specific activity (SA) of CDK1 (CDK1SA), but not CDK2, significantly predicted distant metastasis (concordance index=0.69, 95% confidence interval (CI): 0.55-0.79, P=0.036). Cutoff derivation by maximum log-rank statistics yielded a threshold of CDK1SA at 11 (SA units, P=0.029). Accordingly, 59% of patients were classified as high-risk (CDK1SA ≥11). Cox proportional hazard analysis revealed CDK1SA as independent prognostic variable (hazard ratio=6.2, 95% CI: 1.44-26.9, P=0.012). Moreover, CKD1SA was significantly elevated in microsatellite-stable tumours.

Conclusion: Specific activity of CDK1 is a promising biomarker for metastasis risk in stage II colon cancer.

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Figures

Figure 1
Figure 1
Prognostic performance of the specific activities of CDK1 and CDK2. (A) All cases (n=254) plotted on a scatter diagram with logarithmic scales according to CDK1SA and CDK2SA, respectively. Red symbols: patient with distant metastasis, black symbol: no metastasis. (B and C) Time-dependent ROC analysis against CDK1SA (B) or CDK2SA (C). Thick line: concordance index, thin line: 95% CI. Concordance index was 0.69 for CDK1SA (95% CI: 0.55–0.79, P=0.036), and 0.51 for CDK2SA (95% CI: 0.25–0.66, P=0.57). (D) Derivation of an optimal CDK1SA cutoff value. The maximum log-rank test statistic was obtained when CDK1SA was 11 or 18 (maU eU–1).
Figure 2
Figure 2
Analysis of distant metastasis-free survival and cause-specific survival. (A) Patients classified in the high-risk group (based on CDK1SA >11 maU eU–1) had a significantly worse distant metastasis event rate as compared with the low-risk group (HR=6.2, 95% CI: 1.45–26.9, P=0.0049; exact conditional Monte-Carlo P-value=0.029). (B) Patients classified in the CDK1SA-based high-risk group had a significantly lower cause-specific survival (HR=7.62, 95% CI: 1.80–32.2, P=0.001).
Figure 3
Figure 3
Correlation between CDKSAs and Ki-67 index (percent of Ki-67-positive cells of all CK20-positive tumour cells). Cases were plotted on a scatter diagram according to Ki-67 index against CDK1SA (left), or CDK2SA (right). Red circle: tumour with distant metastasis. Ki-67 showed a weak but significant positive correlation with CDK2SA (Spearman’s ρ=0.17, P=0.016), but not with CDK1SA (Spearman’s ρ=0.04, P=0.54).
Figure 4
Figure 4
Association of CDK1SA-based risk stratification with microsatellite-stable phenotype. Among the patients with a stable microsatellite phenotype (MSS), 62% (102 out of 164) were classified in the high-risk group based on CDK1SA. On the other hand, 47.5% (28 out of 59) of the patients with high MSI (MSI-H) were classified as high-risk, based on the CDK1SA threshold (χ2-test, P=0.0465).
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