Estrogens in the Environment III

During the 13 years which have passed since the p53 protein was first identified, studies of the p53 gene have gained in scientific importance, leading to discoveries with major clinical implications. Although originally classified as an oncogene, more recent results from a number of studies have established that the p53 gene exhibits properties conssistent with a tumour suppressor gene. Mutations and deletions in p53 have emerged as the most common genetic changes found in cancer cells. The events leading to the classification of p53 as a tumour suppressor gene are reviewed by Lane & Benchimol, 1990. The p53 gene includes five evolutionarily conserved domains common to mammals, amphibians, birds and fish (Soussi et al., 1990). Mutations seen in sporadic tumours are largely missense mutations, clustering within conserved domains II-V encompassing exons 5-8. In particular, at least three mutational hot-spots at codons 175, 248 and 273 have emerged. Mutations at these hot-spots are characteristically transitions at CpG dinucleotides. Cancers originating from various specific tissue sites differ with respect to the distribution and frequency of mutations at these hot-spots. Holstein et al., 1991 and Caron de Fromental and Soussi, 1992, have reviewed these patterns of mutations in human cancers. In November 1990 Malkin et al. reported germline mutations in p53 in five families with the Li-Fraumeni syndrome (LFS). LFS was first defined on the basis of familial clusters of cancers in association with childhood soft tissue sarcomas. In these families there was a high incidence of pre-meno-pausal breast cancer, sarcomas and other cancers occurring at unusually early ages in the relatives of the childhood sarcoma cases (Li & Fraumeni, 1969). In 1988 Li et al. published a study of 24 families with the syndrome. Among these families, in addition to soft tissue sarcoma and early onset breast cancer, osteosarcoma, brain tumours, leukaemia and adrenocortical carcinoma also occurred to excess. The mutations in LFS families reported by Malkin et al. (1990) all occurred in exon 7 and were located between codons 245 and 258 within one of the evolutionarily conserved domains. Shortly after, a case report of a sixth LFS family with a germline mutation within the same stretch of codons was published (Srivastava et al., 1990). These remarkable results indicated that germline mutations in the p53 gene were responsible for the high incidence of cancers in these LFS families. Furthermore, the restricted distribution of the germ-line mutations implied that the association with …