CAN WE PREDICT SOLAR ULTRAVIOLET-RADIATION AS THE CAUSAL EVENT IN HUMAN TUMORS BY ANALYZING THE MUTATION SPECTRA OF THE P53 GENE

The tumour suppressor gene, p53, has proved to be one of the genes mos t often modified in human cancers. These alterations consist mainly of point mutations located in the evolutionarily conserved sequences whi ch render the protein inactive for its normal biological functions. In fact the p53 gene presents nearly 300 potential mutation sites whose analysis should enable the correlation of specific mutation spectra wi th different causal agents in cancer development. In this study we hav e analysed the mutation spectrum of the p53 gene in skin tumours from normal individuals and repair-deficient xeroderma pigmentosum (XP) pat ients in comparison with mutations found in internal cancers. Point mu tations are mainly GC --> AT transitions in skin tumours (74% in non-X P, 87% in XP), and also to a lesser extent in internal tumours (47%) w here, however, they are mainly located at CpG (63%) sequences probably due to the deamination of the unstable 5-MeC. Moreover, mutations are targeted at py-py sequences in over 90% of skin tumours whereas the d istribution of mutations in internal malignancies is proportional to t he frequency of py-py sites (61%) and other sequences (39%) at mutable sites. Indeed, in XP skin tumours 100% of the mutations are targeted at py-py sequences and 55% of these are tandem CC --> TT transitions c onsidered as a signature of UV-induced lesions. In skin tumours from n ormal individuals, 14% of the p53 mutations are double mutations and a s in XP skin tumours all these are CC --> TT transitions. In contrast, internal tumours rarely contain tandem mutations (0.8%), and of these only 2/14 were CC --> TT transitions. Finally, nearly all (95%) of th e mutations in XP are located on the non-transcribed strand while inte rnal or non-XP skin tumours do not show this strand bias. Hence, the m utation spectrum analysed in XP skin tumours also demonstrates for the first time the existence of preferential repair in humans. In conclus ion, the specificity of UV-induced p53 mutation spectra in skin tumour s shows that this gene is a particularly appropriate candidate for the correlation of mutation spectra with specific damaging agents.