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Published on: January 5, 2017
Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer
Qiong Wu1, Michèle J Hoffmann, Florian H Hartmann
1Dept. of Urology, Heinrich Heine University, Düsseldorf, Germany. wu_qiong@yahoo.com
Background:
Amplifications at 6p22.3 are prevalent in advanced stage bladder cancer (TCC). Previous studies have identified SOX4, CDKAL, and E2F3 as targets of this amplification and therefore potential oncogenes, but the more telomeric DEK gene too has been reported as overexpressed and amplified. We have therefore investigated whether the intermediate region harboring the oncogene candidate ID4 is also part of the amplicon.
Results:
Expression of E2F3, DEK, and ID4 was investigated by real-time RT-PCR in 28 TCC compared to 6 normal bladder tissues and in 15 TCC cell lines compared to cultured normal urothelial cells. Expression of E2F3 as well as DEK increased on average in tumor vs. normal tissues (3-fold and 2.5-fold, resp.), but only the increase for E2F3 was statistically significant (p = 0.039). ID4 overexpression was observed in selected specimens. Each of the three genes was overexpressed in several cell lines, up to 150-fold (ID4), 30-fold (E2F3), and 9-fold (DEK), but these increases were not correlated to each other. Instead, moderate (DEK) to excellent (ID4) correlations were observed with copy number increases of microsatellites near each gene. Microsatellite copy number increases were highly heterogeneous across the investigated several Mb region revealing at least three subregions of amplification.
Conclusion:
Extending previous reports, our data indicate that the 6p22.3 amplicon in TCC is highly heterogeneous and targets several genes in a variable fashion. Among these, expression of E2F3 and DEK appear to be generally increased in TCC, with additional increases caused by amplifications. In contrast, over-expression of ID4, which is normally predominantly expressed in testes and brain, appears to depend more strictly on gene amplification. Accordingly, the effect of amplifications at 6p22.3 in bladder cancer is expected to be non-uniform, thereby contributing to the highly variable biological and clinical behavior of advanced stage tumors. ID4 is a potential oncogene in a small subset of bladder cancers.
Insights
Amplifications in bladder cancer target multiple genes heterogeneously. While E2F3 and DEK show general expression increases, ID4 overexpression is linked to gene amplification, suggesting it
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Amplifications at 6p22.3 are common in advanced urothelial carcinoma (TCC).
- Previous studies identified SOX4, CDKAL, and E2F3 as targets of this amplification.
- The DEK gene and the ID4 oncogene candidate in the intermediate region were also investigated for amplification and overexpression.
Purpose of the Study:
- To investigate if the ID4 gene is part of the 6p22.3 amplicon in TCC.
- To analyze the expression patterns of E2F3, DEK, and ID4 in TCC and normal bladder tissues.
- To correlate gene expression with copy number alterations in the 6p22.3 region.
Main Methods:
- Real-time RT-PCR was used to assess gene expression in 28 TCC and 6 normal bladder tissues.
- Gene expression was also analyzed in 15 TCC cell lines and normal urothelial cells.
- Microsatellite copy number increases were analyzed to identify amplification subregions.
Main Results:
- E2F3 and DEK showed average increases in tumor vs. normal tissues (3-fold and 2.5-fold, respectively), with only E2F3 being statistically significant.
- ID4 overexpression was observed in selected specimens and cell lines, with increases up to 150-fold.
- Gene expression increases were not correlated with each other but showed moderate to excellent correlations with microsatellite copy number increases, revealing at least three amplification subregions.
Conclusions:
- The 6p22.3 amplicon in TCC is heterogeneous, targeting multiple genes variably.
- E2F3 and DEK expression are generally increased in TCC, with amplifications contributing further.
- ID4 overexpression is more strictly dependent on gene amplification, identifying it as a potential oncogene in a subset of bladder cancers.
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