الفهرس 
Biomarkers used in diagnosis of prostate disordersOnly 14 pages are availabe for public view
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Abstract
Prostate cancer (PCa) is the sixth leading cause of cancerrelated deaths among men. Men above 45 years old are prone to benign prostatic hyperplasia (BPH), which may progress into prostate cancer (PCa). Androgens are male sex hormones required for the normal development, growth, and differentiation of the normal prostate gland. These hormones exert their functions through their interaction with the nuclear, ligand dependent androgen receptor called human androgen receptor (hAR). This receptor is a member of a superfamily of ligand-activated nuclear transcription factors. The hAR gene is located on the X chromosome at the locus Xq11-Xq12, and consists of 8 exons. The gene is translated into a hAR protein with three major functional domains including: (i) the N-terminal domain (NTD), (ii) the DNA binding domain (DBD) and (iii) the Cterminal ligand binding domain (LBD). The three domains are important for the normal receptor function. Previously we investigated the restriction integrity of the hAR exons corresponding to the LBD. Our investigations had revealed the integrity of exons 4– 6 in patients with BPH or PCa. Exons 7 and 8, however have kept their constitutional pattern only in BPH patients. Hph1 restriction site showed an abnormal RFLP pattern in 40% and 26.7% of PCa patients in exons 7 and 8 respectively. Also, Tsp45I demonstrated restriction polymorphism in 20% and 13% of PCa patients. Compared to other hAR domains, DBD, which is the focus of this thesis, is more conserved and contains less mutations. To our knowledge it was not subjected to a precise genetic abnormality studies like other domains. Mutations in the hAR-DBD, have been reported and have been shown to selectively affect transactivation and transrepression functions of the hAR on different promoters and reduced DNA-binding ability and some mutations were associated with partial or complete androgen insensitivity. In continuation of the genetic screening of the entire hAR gene we undertaking, this study to investigate the restriction integrity of the DBD and the flanking sequences in patients diagnosed with prostate disorder categorized according to the degree of progression towards prostate cancer. Patients population included those diagnosed with prostatitis, BPH, BPH associated with prostatitis and patients histologically diagnosed with prostatic adenocarcinoma. In addition to the serum PSA level, exons 2 and 3 were targeted by amplification and subsequent RFLP analysis using RsaI, Hph1 and BbV1 restriction enzymes. The amplification was performed to include the DBD in addition to the flanking sequences. This explains why the amplification products of exons 2 and 3 (318bp+257bp) are longer than the known size of the DBD. In parallel, the flow cytometric analysis was performed to detect any changes in the cell population in the S phase. The data revealed that: • The highest mean age was observed in patients with poorly differentiated prostatic adenocarcinoma (72±1.8 years) followed by patients with BPH associated with prostate inflammation (69± 3.4 years). • There were no statistically significant differences (P>0.05) between the mean ages of patients in different groups. • Patients with prostate adenocarcinoma had a higher levels of serum PSA levels compared to other groups. • Restriction fragment length polymorphism (RFLP) analysis of exon 2 using BbvI showed 2 abnormal restriction patterns in some patients in addition to the BbvI constitutional pattern. • The restriction enzyme HphI did not show any restriction abnormalities in exon 2 • RsaI showed a restriction abnormality in exon 3 • Flow cytometry did not show significant differences in the Sphase fraction among groups (p ˃ 0.05). In conclusion, the data demonstrates that although the DNA binding domain is known to be conserved region, progression of prostate towards malignancy is associated some RFLP abnormalities and the S phase fraction was able to discriminate between prostate malignant and premalignant cases.