Abstract
Purpose
To assign functional properties to gene expression profiles of cervical cancer stages and identify clinically relevant biomarker genes.
Experimental design
Microarray samples of 24 normal and 102 cervical cancer biopsies from four publicly available studies were pooled and evaluated. High-quality microarrays were normalized using the CONOR package from the Bioconductor project. Gene expression profiling was performed using variance-component analysis for accessing most reliable probes, which were subsequently processed by gene set enrichment analysis.
Results
Of 22.277 probes that were subject to variance-component analysis, eleven probes had low heterogeneity, that is, a W/T ratio between 0.18 and 0.38. Seven of these probes are induced in all cervical cancer stages: they are GINS1, PAK2, DTL, AURKA, PRKDC, NEK2 and CEP55. The other four probes are induced in normal cervix: P11, EMP1, UPK1A and HSPC159. We performed GSEA of 9.873 probes exhibiting less variability, that is, having a W/T ratio of <0.75. Repeatedly, significant gene expression signatures were found that are related to treatment using angiocidin and darapladib. Additionally, expression signatures from immunological disease signatures were found, for example graft versus host disease and acute kidney rejection. Another finding comprises a gene expression signature in stage IB2 that refers to MT1-MMP-dependent migration and invasion. This gene signature is accompanied by gene expression signatures which refer to ECM receptor-mediated interactions.
Conclusion
Analysis of cervical cancer patient gene expression data reveals a novel perspective on HPV-mediated transcription processes. This novel point of view contains a better understanding and even might provide improvements to cancer therapy.
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Acknowledgments
We wish to acknowledge the kind help and insightful correspondence with B. Bachtiary and M. Pintilie, especially M. Pintilie is sincerely thanked for providing the R code of the variance-component analysis. We like to thank Scott Preiss for critical comments on the initial manuscript and for sharing his competence in HPV research.
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The authors declare that they have no conflict of interest.
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Statement of translational relevance: At present, there are no generally accepted biomarkers for cervical cancer available. Here, we utilize an already approved approach for biomarker discovery on a large-scale pooled microarray dataset. Eleven highly reliable probes resulting from this analysis feature cervical cancer biomarker properties. Moreover, overlap between our gene signatures and those from studies available in the literature affirm the utility of this approach. However, the most striking findings are that the gene expression signatures were associated with signatures observed for patients treated using angiocidin and darapladib. Previous studies have shown that angiocidin induces differentiation of monocytes to macrophages and induce anti-tumoral action, whereas darapladib exerts anti-inflammatory action. Therefore, we suggest these two agents as potential candidates for novel treatment options in cervical cancer patients.
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Koch, M., Wiese, M. Gene expression signatures of angiocidin and darapladib treatment connect to therapy options in cervical cancer. J Cancer Res Clin Oncol 139, 259–267 (2013). https://doi.org/10.1007/s00432-012-1317-9
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DOI: https://doi.org/10.1007/s00432-012-1317-9