|Title:||Genetic detection of bladder cancer by microsatellite analysis on p16 and p53 tumour suppressor genes in local Chinese|
|Subject:||Hong Kong Polytechnic University -- Dissertations|
Bladder -- Cancer -- Genetic aspects
Bladder -- Cancer -- Molecular aspects
School of Nursing
|Pages:||x, 93 leaves : ill. (some col.) ; 30 cm|
|Abstract:||It is generally believed that carcinogenesis of bladder cancer is a result of accumulation of multiple gene mutations and chromosomal aberrations. In particular, the allelic losses of the chromosomal regions 9p, 9q and 17p are major events in the development of bladder cancer. Genetic analyses have shown that carcinoma in-situ (CIS) contains a spectrum of genetic alterations, such as p53 mutation and loss of heterozygosity (LOH) on chromosomes 3p, 8p, 13q and 17p, where only LOH of chromosome 9, such as deletions of p16 and p15 tumour suppressor genes, is common in non-muscle invasive low grade papillary neoplasms. Thus, if these mutations can be detected in urine specimens with high sensitivity, it can be a non-invasive and reliable routine laboratory test on detecting low-grade papillary neoplasms of urinary bladder. In this study, the incidence of genetic alterations of p16 and p53 tumour suppressor genes in fresh urine specimens and their corresponding histological confirmed Transitional Cell Carcinoma (TCC) biopsies were investigated by microsatellite analysis. In addition, the clinical usefulness of microsatellite analysis on urine specimens for detecting TCC in local Chinese population was assessed. Fourteen highly polymorphic microsatellite markers were selected to map the known tumour suppressor genes p16 and p53 at 9p2l and 17p13 respectively. The microsatellite markers were used to analyse the DNA from leukocytes (considered to be normal controls), urine sediments and corresponding biopsy specimens from 24 patients with TCC. DNA of tumour biopsy specimens was available in 22 of them. PCR analysis was performed followed by polyacrylamide gel electrophoresis and then silver stained. The microsatellite analyses of normal and pathological samples were compared. The analyses were performed twice with highly reproducible results. Only 8 of 24 urine specimens (33%) demonstrated LOH in at least one of the microsatellite marker. The same microsatellite alteration patterns were detected in the corresponding tumour biopsy specimens. Moreover, a much higher percentage of the tumour biopsy specimens showed microsatellite alterations. Sixteen of twenty-two tumour biopsy specimens (73%) showed LOH in at least one of the microsatellite marker. As expected, no microsatellite alterations were found in the normal group in which there was no evidence of bladder cancer. The presence of microsatellite alterations suggests that they are important events in TCC. In addition, no statistical association between the genetic alterations and the tumour stage and grade was observed. Interestingly, the microsatellite markers may be ethnicity restricted. In this study, among 24 Chinese patients, it was found that D9S157, D9S161, D17S921 and D17S969 were the frequent loci that exhibited LOH. None of the tumour sample showed alteration at D9S270, which showed LOH in Greeks. In addition, LOH in D9S171 and D9S162 were frequent in Americans but they were not common in these studied samples. From the results, although there are LOH in cytological urine specimens at different loci, the low sensitivity precludes its use in routine clinical practice in the immediate future. However, the excellent specificity renders it a valuable analysing tool to detect low-grade papillary neoplasms especially for difficult cases.|
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