STABILIZED P53 FACILITATES ANEUPLOID CLONAL DIVERGENCE IN COLORECTAL-CANCER

Mutations in the p53 tumour suppressor gene are amongst the most frequ ent genetic abnormalities acquired in tumours. Recent studies in vitro suggest that mutant p53 destabilises the genome and facilitates devel opment of aneuploidy. Here, in a study of 83 colorectal carcinomas, we demonstrate that alterations in p53 (detected by immunocytochemical s tabilisation) precede and apparently facilitate divergence of aneuploi d sub-clones. Aneuploidy in these tumours (but not those with normal p 53) is predominantly in the subtetraploid range, suggesting that endor eduplication is important in its origin. This association with a speci fic phase of carcinoma progression is not shared by other commonly acq uired genetic abnormalities in these tumours. These observations highl ight the critical role of p53 in the regulation of abnormal chromosome replication and afford an explanation for the association between p53 abnormalities, aneuploidy and biological aggression in cancer.