Can we predict solar ultraviolet radiation as the causal event in human tumours by analysing the mutation spectra of the p53 gene? - PubMed (original) (raw)

Review

Can we predict solar ultraviolet radiation as the causal event in human tumours by analysing the mutation spectra of the p53 gene?

N Dumaz et al. Mutat Res. 1994.

Abstract

The tumour suppressor gene, p53, has proved to be one of the genes most often modified in human cancers. These alterations consist mainly of point mutations located in the evolutionarily conserved sequences which 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 with different causal agents in cancer development. In this study we have analysed the mutation spectrum of the p53 gene in skin tumours from normal individuals and repair-deficient xeroderma pigmentosum (XP) patients in comparison with mutations found in internal cancers. Point mutations are mainly GC-->AT transitions in skin tumours (74% in non-XP, 87% in XP), and also to a lesser extent in internal tumours (47%) where, 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 distribution of mutations in internal malignancies is proportional to the 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 considered as a signature of UV-induced lesions. In skin tumours from normal individuals, 14% of the p53 mutations are double mutations and as 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 the mutations in XP are located on the non-transcribed strand while internal or non-XP skin tumours do not show this strand bias. Hence, the mutation spectrum analysed in XP skin tumours also demonstrates for the first time the existence of preferential repair in humans. In conclusion, the specificity of UV-induced p53 mutation spectra in skin tumours shows that this gene is a particularly appropriate candidate for the correlation of mutation spectra with specific damaging agents.

PubMed Disclaimer

Cited by

Lack of p53 mutations and loss of heterozygosity in non-cultured human melanocytic lesions.
Papp T, Jafari M, Schiffmann D. Papp T, et al. J Cancer Res Clin Oncol. 1996;122(9):541-8. doi: 10.1007/BF01213550. J Cancer Res Clin Oncol. 1996. PMID: 8781568
p53 gene mutation: software and database.
Béroud C, Verdier F, Soussi T. Béroud C, et al. Nucleic Acids Res. 1996 Jan 1;24(1):147-50. doi: 10.1093/nar/24.1.147. Nucleic Acids Res. 1996. PMID: 8594565 Free PMC article.
UVA-induced cyclobutane pyrimidine dimers form predominantly at thymine-thymine dipyrimidines and correlate with the mutation spectrum in rodent cells.
Rochette PJ, Therrien JP, Drouin R, Perdiz D, Bastien N, Drobetsky EA, Sage E. Rochette PJ, et al. Nucleic Acids Res. 2003 Jun 1;31(11):2786-94. doi: 10.1093/nar/gkg402. Nucleic Acids Res. 2003. PMID: 12771205 Free PMC article.
Exome sequencing identifies novel mutation signatures of UV radiation and trichostatin A in primary human keratinocytes.
Shen Y, Ha W, Zeng W, Queen D, Liu L. Shen Y, et al. Sci Rep. 2020 Mar 18;10(1):4943. doi: 10.1038/s41598-020-61807-4. Sci Rep. 2020. PMID: 32188867 Free PMC article.
p53 gene mutation: software and database.
Béroud C, Soussi T. Béroud C, et al. Nucleic Acids Res. 1998 Jan 1;26(1):200-4. doi: 10.1093/nar/26.1.200. Nucleic Acids Res. 1998. PMID: 9399836 Free PMC article.

Can we predict solar ultraviolet radiation as the causal event in human tumours by analysing the mutation spectra of the p53 gene? - PubMed (original) (raw)