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Cyclin E is the Only Cyclin-dependent Kinase 2-associated Cyclin that Predicts Metastasis and Survival in Early Stage Non-Small Cell Lung Cancer¹

Department of Medicine, Hematology and Oncology [C. M-T., K. K., S. D., M. T., W. E. B., H. S.], and Department of Pathology [B. D-D.], University of Münster, 48129 Münster, Germany; Department of Visceral and Vascular Surgery, University of Cologne, 50924 Cologne, Germany [R. M., P. M. S.]; and Division of Hematology/Oncology, Cedars-Sinai Research Institute/University of California at Los Angeles School of Medicine, Los Angeles, California 90048 [G. I., H. P. K.]

Progression through G₁-S transition and S phase of the cell cycle is mediated by cyclin-dependent kinase 2 (cdk2), which interacts with several cyclins. Two of these, cyclin E and cyclin A2 (also known as cyclin A), are overexpressed in many cancers. Cyclin E2 and cyclin A1 are recently discovered cdk2-interacting cyclins that are found in malignant tumor cell lines and in acute myeloid leukemia, respectively. Expression and prognostic role of these cyclins in solid tumors is unknown. Here, we have analyzed expression and prognostic relevance of the cdk2-associated cyclins in non-small cell lung cancer (NSCLC). Fresh-frozen biopsies (n = 70) from completely resected tumors with stage I to IIIA NSCLC were studied. Gene expression was analyzed by quantitative real-time reverse transcription-PCR. Expression levels of cyclin E (P = 0.04) and cyclin A2 (P = 0.004) were significantly higher in the tumor samples than in normal controls. Cyclin A1, cyclin A2, and cyclin E2 expression levels did not have prognostic relevance for survival. The mean survival time associated with low and high levels of cyclin E was 69.4 and 47.2 months, respectively, which was statistically significant (P = 0.03). Differences in survival were particularly pronounced in stages I and II. Cyclin E was also closely associated with the development of distant metastasis (P = 0.01). Finally, we confirmed by immunohistochemistry analyses that cyclin E mRNA expression was closely associated with cyclin E protein expression. In conclusion, cyclin E is a strong independent prognostic indicator in patients with early-stage NSCLC, whereas cyclin E2, cyclin A1, and cyclin A2 do not have a prognostic role in NSCLC.

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