Sary To establish whether p53 mutation precedes or follows clonal divergence in human colorectal carcinomas, 17 tumours were analysed at multiple sites (2-5 each) for single-strand conformation polymorphisms (SSCP) within exons 5-8 of the p53 gene. A previous study had demonstrated subclones of differing DNA pkoidy in these tumours, but all showed immunocytochemical evidence for p53 stabilisation, using the monockal antibody PAb 1801. Mutations within exons 5-8 of p53 were identified by the presence of an abnormally migrating band in 10 of the 17 carcinomas: five in exon 5, four in exon 7 and one in exon 8. In each of these positive cases samples from different parts of the cacino showed identiclW gd migration patterns in SSCP analysis. Similarly, the rm_ainin seven tumours were concordant for absence of band shift across all samples of each tumour. Six SSCP-positive cases contained multiple populations differing in DNA ploidy, while four were homogeneously diploid or aneuploid throughout. Very similar proportions were observed in the SSCP-negtive cases. In four positive tumours the mutation was confirmed by sequencing or through alteration of nucleotide-specific restriction enzyme cleavage. Identical mutations appeared in every sample from the same tumour. The results provide unequivocal evidnce that the same mutant allele of p53 is present throughout each tumour bearing a mutation, regardless of the clonal variation identified by analysis of DNA ploidy. We conclude that in colorectal tumorigenesis mutation of p53 occurs as a single event which precedes and may facilitate the aneuploid clonal divergence of carcinomas.
demonstrated clonal genetic alterations resulting in loss of heterozygosity for one or more markers. Seven of the clonal genetic alterations on chromosome 11 were specific to the long arm, and the overlap between-these and other allelic deletions suggests that a suppressor gene(s) relevant to cervical carcinoma maps to chromosome 11q22-q24.
We are presently involved in a project to investigate the use of flow cytofluorometry in assessing, by means of serial biopsies, the response to radiotherapy of tumours of the uterine cervix. This technique enables changes in the DNA content profiles and content of proliferating cells in the tumour biopsies to be determined at intervals as therapy progresses. A means has been devised to quantitate the content of hyperdiploid cells, hypertetraploid cells, and dead and dying cells, by computer analysis of DNA vs. RNA scattergrams obtained by flow cytofluorometric analysis. Plotting of these parameters for the serial biopsies vs. time since start of tumour irradiation presents a graphical indication of the response of the tumour to irradiation. Over 100 patients (stage Ib and IIa) have been followed during intracavitary (Cathetron) therapy with parallel flow cytofluorometric analysis and histopathological assessment of serial biopsies. Patterns are beginning to emerge from these analyses which promise to indicate within 14-21 days and sometimes earlier the extent of radioresponsiveness of the tumour. These patterns may also be of assistance in planning modified dose fractionation schedules to obtain improved therapeutic ratios.
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