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A CDK2 activity signature predicts outcome in CDK2-low cancers

Oncogene volume 36, pages 2491–2502 (2017)Cite this article

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Abstract

The role of cyclin-dependent kinase 2 (CDK2) in cancer is controversial. A major hurdle is the availability of tools to easily assess its activity across many samples. Here, we introduce a transcriptional signature to specifically track CDK2 activity. It responds to genetic and chemical perturbations in the CDK-RB-E2F axis, correlates with mitotic rate in vitro and in vivo and reacts rapidly to changes in CDK2 activity during cell cycle progression. We find that CDK2 activity is specifically elevated in human testes, mirroring its critical function in mice, and report very distinct profiles across human cancers. Increased CDK2 activity decreases risk in colon cancer, but elevates poor outcome two- to fivefold in specific tumors, including low grade glioma, kidney, thyroid, adrenocortical and prostate cancer. These are typically ‘CDK2-low’ cancers, suggesting that above a certain threshold CDK2 promotes progression, but further increases do not influence outcome. Multivariate analysis revealed that the CDK2 signature is the most important predictive feature in these cancers versus dozens of other clinical parameters, such as tumor grade or mitotic index. Thus, transcriptome data provides a novel, straightforward method to monitor CDK2 activity, implicates key roles for the kinase in a subset of human tissues and tumors and enhances cancer risk prediction. The strategy used here for CDK2 could be applied to other kinases that influence transcription.

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Acknowledgements

We thank G Bader, F Roth and J Wrana for helpful comments. This project was funded by grants to RB from the Canadian Institutes for Health Research (CIHR), Foundation Fighting Blindness Canada, Krembil Foundation, Ontario Institute for Cancer Research through funding provided by the Government of Ontario and the Terry Fox Research Institute. SRM was supported by scholarships from Peterborough KM Hunter Foundation, CIHR (Vanier Graduate Scholarship) and the CIHR Biological Therapeutics Program.

Author contributions

SRM and RB designed the experiments and drafted the manuscript. MP and MA gathered samples and performed microarray on retinal samples. The data analysis was performed by SRM. SRM and RB discussed and revised the manuscript. All authors read and approved the final manuscript.

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  1. Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Sinai Health Systems, Toronto, Ontario, Canada

    S R McCurdy, M Pacal, M Ahmad & R Bremner

  2. Department of Laboratory Medicine and Pathobiology, Department of Ophthalmology and Vision Science, University of Toronto, Toronto, Ontario, Canada

    S R McCurdy & R Bremner

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  1. S R McCurdy
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Correspondence to R Bremner.

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McCurdy, S., Pacal, M., Ahmad, M. et al. A CDK2 activity signature predicts outcome in CDK2-low cancers. Oncogene 36, 2491–2502 (2017). https://doi.org/10.1038/onc.2016.409

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