Year: 2008
Type: dissertation
Study design: Observational Study
Abstract: The aims of this study were: (i) to determine the association between p53, bcl-2, pRb, \np21, cyclin A and p-glycoprotein immunoexpression and prognosis, and (ii) to \ndetermine the frequency of loss of heterozygosity and microsatellite instability at 11 p, \n16q and mismatch repair gene loci and their association with prognosis, in \nnephroblastomas in South African children. \nThere were 138 cases (111 of whom received preoperative chemotherapy) in the \nimmunohistochemical study and, 70 cases (48 with preoperative chemotherapy) in \nthe microsatellite study. The following monoclonal antibodies were used after heat \ninduced epitope retrieval; p53, bcl-2, pRb, p21, cyclin A and p-glycoprotein. Six \npolymorphic microsatellite markers were selected from the 11p region, 5 from the 16q \nregion and 6 from the loci of known mismatch repair genes. Automated fluorescent \nDNA technology was used in the analysis. The results of the immunohistochemical \nand microsatellite studies were correlated with patient age, gender, preoperative \nchemotherapy, SlOP histological classification, SlOP histological risk group, \nclinicopathological stage, patient outcome and survival using X2 \n, Fisher's exact test, \nCox regression model and Kaplan-Meier estimates. \nThe majority of patients presented with advanced disease. Anaplastic tumours and \nhigh-risk histology were associated with high disease stage. Mortality was directly \nrelated to increasing stage and histological risk group. Multivariate analysis showed \nthat clinicopathological stage was the only factor significantly associated with survival \n(p<0.001) (hr=5.6, 95%CI: 2.1-14.9). \nHigh expression of p53 was more frequent in anaplastic tumours suggesting that p53 \nmutations are common events in this tumour type (p<0.001). Despite the strong \nassociation with tumour histology, there was no association with stage. Although p53 \nexpression was found to be a predictor of survival in the univariate analysis this was \nnot retained in the multivariate analysis. Tumours treated with preoperative \nchemotherapy showed higher bcl-2 immunoreactivity (p=0.027 but lower levels of pRb \n(p=0.040) and cyclin A expression (p<0.001). All anaplastic tumours showed high \nexpression of pRb compared to the other histological types (p=0.003). Expression of \nxxii \npRb was significantly associated with survival in the univariate analysis but not in the \nmultivariate analysis. High cyclin A expression was associated with high risk histology \n(p<0.001). Cyclin A expression was found to be a significant predictor of survival in \nboth the univariate (hr=1.7; 95%CI 1.2-2.4; p=0.002) and multivariate analyses \n(hr=1.7; 95%CI1.1-2.7; p=0.032). Although tumours with high risk histology were \nmore likely to express high levels of p-glycoprotein, this did not reach significance. \nLOH at 11 p was seen in 64.7% of 68 informative cases. LOH at 11 p13 was more \nfrequent than LOH at 11p15. LOH for both 11p13 and 11p15 was found in 39.7% of \nall tumours. MSI at 11 p was seen in 22.1 % of informative cases. The majority \nshowed MSI for one marker only. LOH 16q was seen in 66.7% of 66 informative \ncases. MSI at 16q was seen in 16.7% of cases. LOH for 016S496 and 016S520 \nappear to be related to tumour histology and risk group. The most frequent locus for \nLOH was 16q21-22, which is known to harbour important genes, such as, E2F4 and \nE-cadherin. LOH for MMR markers was seen in 43.5% of 69 informative cases. MSI \nwas seen in 11.6% of tumours. In the multivariate analysis there was no significant \ncorrelation between LOH at any of the loci studied and survival. There were no \ntumours with high frequency MSI. Low frequency MSI was of no clinicopathological \nsignificance. \nThe following conclusions are made: (i) p53 mutations determined by high p53 \nexpression is a frequent finding in anaplastic tumours, (ii) Bcl-2 may play a role in the \nchemoresistance of nephroblastomas, (iii) Rb gene alterations are not important in \nthe development of nephroblastoma and anaplasia, (iv) Cyclin A expression is an \nindependent predictor of survival, (v) p-glycoprotein may be responsible for the \nchemoresistance in a proportion of nephroblastomas, (vi) MSI is a rare occurrence in \nnephroblastoma and does not play a role in the development of nephroblastoma, (vii) \nLOH at 11 p and 16q are frequent findings in nephroblastomas, (viii) LOH for the \nspecific 16q markers (016S496 and 016S520) may have an important prognostic role \nin nephroblastoma.
Author: Dhirendra Govender
Language: English
Topic: Renal and related cancers
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Pfizer
OpenAlex ID: W2284163986