31st annual meeting of the British Association of Cancer Research and the 5th annual meeting of the Association of Cancer Physicians, 19–22 March 1990

1990 British Journal of Cancer  
Evidence has been accumulating for loss of genetic information associated with various human malignancies. This evidence has been based upon cytogenetic analyses and restriction fragment length polymorphism (RFLP) analyses. Using these techniques, deletion of discrete regions of specific chromosomes have been detected. Human cancers have been associated with specific deletions on single chromosomes (for example, retinoblastomas) or multiple chromosomes (for example, colorectal carcinomas).
more » ... deletions have been interpreted as inactivation of tumour suppressor genes. With few exceptions (rb-l and p53) the genes have not been cloned and linkage analysis data are not available. To provide functional evidence for unknown and putative tumour suppressor genes, we have developed techniques for single chromosome transfer. Data were presented indicating tumour suppression via monochromosome transfer. In most cases, the predicted chromosome had a tumour-suppressing effect. In others, for example, neuroblastoma, this was not the case. Furthermore, we have been able to dissociate the induction of differentiation from tumour suppression in neuroblastoma. Recent refinements of the microcell transfer technique have allowed us to transfer portions of single chromosomes, thereby, more finely mapping the region responsible for tumour suppression. p53 as an oncogene and a tumour suppressor gene. Different point mutations in p53 in human and murine cancer exert a common effect on the proteins conformation and function. The human p53 gene is located on chromosome 17p. Recent studies have shown that this is a frequent site-of allele loss in many human tumours including lung, colon, breast, and brain tumours. Histological staining using a panel of new anti-p53 antibodies isolated in our laboratory has shown that overexpression of the p53 protein is present in over 50% of primary lung and breast tumour biopsies. Similarly at least 30% of colon cancer samples showed high level expression of p53 protein. Work with cell lines has shown that overexpression of the p53 protein is synonymous with mutation. Since using a new PCR based strategy, we found that six out of six breast cancer cell lines that overexpressed p53 were only expressing mutant RNA. In agreement with the results from Vogelstein's laboratory, all of the mutations were point missense mutations that altered evolutionarily conserved amino acids. These results were extended to direct sequencing of mRNA from lung biopsies. All histologically positive tumours were found to be expressing mutant p53 mRNA, whereas no mutation was found in a histologically negative tumour. These results suggest that mutation of p53 is the most common genetic event so far deted in human cancer. A new monoclonal antibody to p53 only immunoprecipitates p53 encoded by mutant genes. Using this antibody we established that t-he different mutations in p53 exert a common effect on the proteins conformation. The mutant proteins behave as both gain of function mutants, in that they have acquired a dominant transforming function, and loss of function mutations, in that they have lost tumour suppressor activity. One way to reconcile these findings is to suggest that the mutant proteins act directly to inactivate wild type p53 function. This leads to an attractive model of p53 mutation in human cancer. Results on the inhibition of SV40 DNA synthesis by mutant and wild type p53 provide a powerful paradigm for the normal function of p53 as a suppressor of cell growth.
doi:10.1038/bjc.1990.324 fatcat:g6a4kmnw6rc6hkqk2v6binev2q