Bott, S.R.J.; (2006) Molecular genetic predictors of prostate cancer progression after radical prostatectomy. Doctoral thesis , University of London.

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Abstract

Objectives To identify genetic markers to predict biochemical outcome after radical prostatectomy and in a separate study to assess methylation, an epigenetic change, in metastatic prostate cancer cell lines. Materials and Methods One group of patients with PSA relapse and another non-relapse group were matched. DNA was extracted from the radical prostatectomy specimens, amplified using thirty microsatellite markers and genotyping performed. PC3, LNCaP and DU145 metastatic prostate cancer cell lines and control cell lines were cultured in the demethylating agent 5-Aza-2 deoxycytidine (5AzaCdR), in parallel with untreated cells. p21WAF,/CIP1 mRNA expression was analysed by RT-PCR. DNA from untreated cell lines was modified with sodium bisulphite and p21nAhI clpl promoter sequencing performed. Results Allelic imbalance was significantly more common in the relapse than the non-relapse group at 10pl2.1(D10S211) (35% vrs 5%, p=0.03). Several markers showed a marked but not statistically significant difference between the two groups including: D1S158, D1S422, D2S222, D5S500, D6S314, D8S136, NEFL, D11S2000, D12S89, D12S1697, D13S269, D15S1232, D16S413 and D18S541. RT-PCR demonstrated p2 HAhLClpl was expressed at low or undetectable levels in metastatic prostate cancer cell lines but was reactivated by treatment with 5AzaCdR. Sequence analysis of the promoter revealed several sites of methylation at the 5' end of a CpG island in the PC3, LNCaP and DU145 cancer cell line DNA, including at a STAT1 binding site. Conclusions A significant association between loss of a locus at chromosome 1 Opl2.1 and biochemical progression after radical prostatectomy was found. p21 expression was low in metastatic prostate cancer cell lines, but was enhanced by demethylation. Several cytosine residues in the promoter region were methylated, in particular where STAT1 binds. The inhibition of the STAT1 signalling pathway by methylation of the p21WAF1 IPI promoter may inactivate the p21WAFiClpl tumour suppressor gene in prostate cancer.

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