Elsevier

Urology

Volume 102, April 2017, Pages 265.e1-265.e7
Urology

Basic and Translational Science
TOP2A, HELLS, ATAD2, and TET3 Are Novel Prognostic Markers in Renal Cell Carcinoma

https://doi.org/10.1016/j.urology.2016.12.050Get rights and content

Objective

To identify and validate novel prognostic marker genes in clear cell renal cell carcinoma (RCC) that are increasingly expressed during tumor progression.

Methods

Total RNA was isolated from normal renal tissue, primary G1 and G3 tumors, 14 samples each, and 32 metastases from RCC patients. Expression profiles were created using oligonucleotide microarrays. Significant gene expression differences (P < .05) were identified among normal kidney, primary tumor, and metastases. For all filtered genes, univariate survival analysis was carried out. Genes for which lower expression was significantly associated with longer survival were further analyzed using multivariate analysis. Expression of the best candidate markers was further validated in an independent cohort of 55 primary tumors using quantitative real-time polymerase chain reaction.

Results

Fifty-nine genes exhibited increased expression in primary RCC compared with normal kidney, and in metastases compared with primary tumors. In univariate or multivariate survival analysis, upregulation of 15 genes was significant. Expression of 8 genes was validated by quantitative real-time polymerase chain reaction. Survival analysis in an independent cohort of 55 RCC patients based on expression in primary RCC showed that TOP2A (hazard ratio [HR] = 4.3, P = .005), HELLS (HR = 3.7, P = .007), ATAD2 (HR = 3.7, P = .019), and TET3 (HR = 2.8, P = .035) represent independent predictors for cancer-specific survival. The proteins encoded by these genes function as topoisomerase, helicase, chromatin modifier, and methyl cytosine dioxygenase, respectively. They are involved in proliferation, transcription, and epigenetic modification.

Conclusion

High mRNA levels of TOP2A, HELLS, ATAD2, and TET3 are independent predictors of poor outcome in RCC patients and may be used for individual risk-adapted therapy in the future.

Section snippets

Patient Tissue

Primary RCC tumors and metastases samples were obtained from clear cell RCC patients undergoing partial or radical resection of RCC at 1 of 2 clinical centers in Germany. Microarray data were generated from a total of 74 samples, that is, 14 normal tissues from tumor-bearing kidneys, 28 primary tumors, and 32 metastases (different sites including lymph node, adrenal gland, lung, and liver). An independent set of 74 samples, that is, 19 normal tissues from tumor-bearing kidneys and 55 primary

Genes Increasingly Expressed During Tumor Formation and Metastasis

Among the 7093 most variably expressed transcripts on the microarray, 3152 showed a more than 2-fold higherexpression in primary tumors when compared with normal kidney tissues (P < .05), whereas 4000 exhibited a more than 2-fold higher expression in metastases in comparison with primary tumors (P < .05; Fig. 1A). The overlapping list of 59 probe sets was used to establish a heat map of gene expression for the 3 tissue types analyzed (Fig. 1B, Supplementary Table S2). This gene set was highly

Discussion

During the last decade, gene expression analysis has become a widely used tool in oncological research. Various strategies have been used to identify prognostic markers based on gene expression profiles from tumor tissue samples. One approach is to analyze known gene networks and pathways that are important for survival and progression of tumor cells. In a previous study, we showed that epithelial mesenchymal transition plays an important role in RCC biology, and that epithelial mesenchymal

Conclusion

TOP2A, HELLS, ATAD2, and TET3 are novel prognostic markers for poor outcome in RCC patients that might help optimize the individual therapeutic and follow-up strategy of RCC patients based on their risk stratification. Further studies are needed to validate these findings and to explore if these genes could be used as therapeutic targets in the future.

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    Financial Disclosure: The authors declare that they have no relevant financial interests.

    Funding Support: The study was supported by grants from Deutsche Krebshilfe (German Cancer Aid, grant number 106141) and from Chinese Scholarship Council (CSC, grant number 2011627052).

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