DNA Methylation and TMPRSS2-ERG Fusion Status in Patients with Prostate Cancer from The Republic of North Macedonia

Prostate cancer is the second leading cause of male deaths in the Western world and the most commonly detected cancer in males. Recent studies have pointed out that DNA methylation and TMPRSS2-ERG fusion transcript, have a high presence among prostate tumor cells. It is estimated that these two molecular mechanisms could be used as potential markers for early detection of malignancy, and/or progression of prostate cancer disease.

The study aimed to test the presence of the DNA methylation and TMPRSS2-ERG fusion transcript in patients with prostate cancer, as a baseline database for further genetic examination. This prospective clinical study focused on a random sample of 88 patients with prostate carcinoma. For the detection of methylation status in 26 tumor suppressor genes (TP73, CASP8, VHL, RARB, MLH1, RASSF1, FHIT, APC, SLC9A2-2, ESR1, CDKN2A, CDKN2B, DAPK1, KLLN, PTEN, CD44, GSTP1, ATM, CADM1, CDKN1B, CHFR, BRCA2, CDH13, HIC1, BRCA1 and TIMP3), in CaP patients the Multiplex Ligation-Dependent Probe Amplification (MLPA) analyses was performed. All samples were conducted on a Real-time PCR analysis for the detection of the TMPRSS2-ERG fusion transcript. Additionally, the data from the histopathology results of tissues, and level of prostate-specific antigen (PSA) in blood were used.

Genome-wide DNA methylation profiles were detected in 10 out of 26 genes: GSTP1was found in 53,4 % of samples, RARB in 44,32%, RASSF1 in 63,6%, APC in 42%, CDH13 in 39,7%, CASP8 in 25%, CD44-12,5%, TIMP3-2%, ESR1-9% and CADM1-1%. Cohen’s (κ) fair agreement test has shown a linear positive moderate correlation between PSA level and 4 genes (RARB, APC, GSTP1, and CDH13), and a significant linear positive moderate correlation between Gleason Score and 9 methylated genes (GSTP1, RARB, RASSF1, APC, CDH13, CASP8, IMP3, ESR1, and CADM1), except for gene CD44. TMPRSS2-ERG fused transcript was detected in 32 out of 88 (36,4%) of the samples. There were no significant differences between patients with/without detected TMPRSS2-ERG fusion related to Gleason score and PSA level. In conclusion, additional studies need to be performed in appropriately powered clinical cohorts that will define the positive diagnostic meaning of TMPRSS2-ERG fusion transcript, point to the sites in the genome that are under the influence of DNA methylation, in that manner offering additional information for further management of the CaP disease.