Ajayi, A.A.; (2006) Investigation of a tumour suppressor gene at chromosome 10q23.3 in prostate carcinoma. Doctoral thesis , University of London.

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Abstract

Using various molecular genetic techniques, attempts have been made to identify a tumour suppressor gene (TSG) in prostate carcinoma. This gene will act as a genetic marker to identify patients at risk of disease progression from prostate cancer. The region at chromosome 10q23-24 is postulated to contain a TSG that plays an important role in the development and progression of tumours as it is deleted in a number of cancers including glioblastomas, endometrial and prostate cancer. In glioblastomas, chromosome 10 is partially or entirely deleted in approximately 90% of tumours. The TSG called Pten has been identified on chromosome 10 in the region 10q23.3. The significance of loss of the Pten gene in prostate cancer is unknown. In this thesis, the clinical significance of single nucleotide polymorphisms (SNP'S) in the chromosomal region 10q23-24 was evaluated. Comparisons in the distribution of polymorphisms between Ninety-five prostate cancer patients and forty-three non-prostate cancer patients were made. Three intronic polymorphism markers within the Pten gene were used: a single-base A >G substitution in intron A, 96 bp upstream of exon 2. A 5-bp ATCTT insertion / deletion in intron D, 110 bp downstream of exon 4 and a single-base T >G substitution in intron H, 32 bp downstream of exon 8. This study did not isolate any particular trend in polymorphism distribution in the Pten gene when comparisons were made between the two study groups. The significance of loss of Pten gene in thirty-four prostate cancer patients was evaluated using four highly informative microsatellite markers: D10S541, D10S2492, D10S1765 and AFMa086wg9 located within and around the Pten locus. DNA was extracted from prostate cancer cells following microdissection of archival paraffin embedded radical prostatectomy specimens. Loss of heterozygousity (LOH) studies was performed on matching blood/tissue DNA using these four microsatellite markers. For these case specimens, frequency of allele loss of 48% was found at the D10S541 locus 39% at D10S1765 32% at D10S2492 and 22% at the AFMa086wg9 locus. At all four microsatellite, the mean (range) LOH was 35.25% (22%-48%). Of the 34 case specimens 17(50%) showed LOH in at least one of the informative marker sites. Correlating the significance of this region of LOH with pathological staging and known prognostic indicators in prostate cancer showed that the loss of the Pten gene was associated with late stage disease and likely to be involved in disease progression in prostatic adenocarcinoma.

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