Key Points
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The genes that are most often found when tumour and normal tissues are compared by gene expression are those involved in proliferation.
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Increased expression of the proliferation genes in tumours is often associated with poor prognoses in cancer patients.
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Cell-cycle-regulated genes have been identified by microarray analysis of cells in culture. Contained in this list are genes that are expressed in each cell cycle phase: G1/S, S, G2 and M phases.
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Comparing the proliferation genes found in tumours and cell-cycle-regulated genes found in cultured cells in vitro shows that there is a significant overlap between these two signatures.
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The cell-cycle-regulated genes identified by microarray analysis provide biomarkers of proliferation in both normal cells and tumours. The observation that the proliferation signature is so clearly identifiable indicates that it could be a component of genomic-based clinical diagnostics for cancer patients.
Abstract
When normal tissue and tumour samples are compared by microarray analysis, the biggest differences most often occur in the expression levels of genes that control cell proliferation. However, this difference is detected whenever mRNA samples that are taken from two cell populations with different proliferation rates are compared. Although the exact genes that comprise this 'proliferation signature' often differ, they are almost always genes that are involved in the fundamental process of cell proliferation. Can the proliferation signature be used to improve our understanding of the cell cycle and cancer pathogenesis, as well as being used as a biomarker for cancer diagnosis and prognosis?
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Acknowledgements
The authors would like to acknowledge the following people and institutions: Gavin Sherlock and Howard Y. Chang for critical reading of the manuscript, and members of the Whitfield laboratory for helpful discussions. M.L.W. is supported by Howard Hughes Medical Institute Biomedical Research award to Dartmouth College, the American Cancer Society, and by grants from the V Foundation for Cancer Research and the Scleroderma Research Foundation. M.L.W. is a V Scholar of the V Foundation for Cancer Research. C.M.P. is supported by the National Cancer Institute Breast SPORE programme, by the National Institute of Environmental Health Sciences and by the National Cancer Institute.
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DATABASES
National Cancer Institute
FURTHER INFORMATION
Cancer Gene Census at the Sanger Centre
Human Fibroblast Cell-Cycle Study
Microarray analysis of the NCI60 cell lines
Molecular Portraits of breast cancer
Glossary
- Ki67-labelling index
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Immunohistochemisty is performed on paraffin-embedded tumour samples for the nuclear antigen Ki67. The percentage of tumour cells that are positive for nuclear Ki67 labelling is determined, and this percent-positive frequency is typically predictive of patient outcomes. In general, Ki67-high patients show poor outcomes and Ki67-low patients show better outcomes.
- Fourier analysis
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A mathematical analysis of waves, discovered by the French mathematician and physicist Joseph Fourier (1768–1830). The mathematical technique can represent the data from a time series as a set of mathematical coefficients that are the amplitudes of a set of sine waves of different frequencies. Using such computational methods, one can select genes that show sinusoidal patterns as cells traverse multiple cell cycles.
- G2 DNA damage checkpoint
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DNA damage checkpoints exist to monitor the accuracy of replication fidelity and genome instability that might be caused by errors in replication, metabolic by-products, exogenous agents or extrinsic sources such as ultraviolet light or ionizing radiation. The checkpoint delays cell-cycle progression to allow the cell time for repair of the damaged DNA. The G2 DNA damage checkpoint arrests cells in G2 phase, stopping the cells from entering mitosis.
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Whitfield, M., George, L., Grant, G. et al. Common markers of proliferation. Nat Rev Cancer 6, 99–106 (2006). https://doi.org/10.1038/nrc1802
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DOI: https://doi.org/10.1038/nrc1802
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