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N17 TMPRSS2: ERG gene fusion and epigenetic changes in tumour suppressor genes are associated with clinical markers of poor prognosis in prostate cancer patients

      Introduction and Objectives

      Prostate cancer (PCa) is the most prevalent malignancy of males characterized by the high mortality rates. There is a need for new molecular biomarkers with a significant potential to recognize patients with potentially lethal disease who will benefit from more radical treatment. The most common genetic defect so far described in prostate cancer is the androgen-regulated TMPRSS2:ERG gene fusion. In order to investigate whether epigenetic changes in collaboration with the fusion transcript expression may improve characterization of PCa, we analyzed a wide panel of molecular markers, including TMPRSS2:ERG gene fusion, activation of telomerase gene (hTERT) expression and hypermethylation of eight tumour suppressor genes.

      Material and Methods

      Molecular changes were investigated in clinical PCa samples obtained from radical prostatectomy specimens of 83 previously untreated patients. Reverse transcription (RT) PCR, real-time PCR, and sequencing of cloned product was used for detection and detail analysis of TMPRSS2:ERG gene fusion. hTERT gene expression was analyzed by means of RT-PCR and real-time PCR. Methylation-specific PCR was used for assessment of hypermethylation in promoter regions of tumour suppressor genes GSTP1, RARb, p16, p14, RASSF1, DAPK, MGMT, and ZAC1.

      Results

      Chimeric TMPRSS2:ERG transcript was detected in 57% (47 of 83) of tumours. Expression of telomerase gene was active in 51% of cases. Among the tumour suppressor genes most frequently hypermethylated in PCa were the GSTP1 (61%) and RARb (68%) genes. TMPRSS2:ERG positive tumours tended to be of higher stage (p = 0.04) and higher grade (p = 0.07). The activation of the hTERT transcription was also more frequently (p = 0.01) observed in patients with TMPRSS2-ERG positive tumours. We found a significant positive correlation between frequency of hypermethylation of the GSTP1 gene and tumour grade (p = 0.04), and the frequency of hypermethylation of the RARβ, RASSF1A and GSTP1 genes tend to increase with the increasing stage of tumours. However, no apparent associations between epigenetic changes in analysed tumour suppressor genes and expression of the TMPRSS2:ERG fusion transcript were established in present study.

      Conclusions

      Preliminary results of our study suggest that detection of the TMPRSS2:ERG gene fusion together with epigenetic biomarkers may be used as novel prognostic indicators for PCa distinguishing patients with unfavourable prognosis.