Dumaz N, Stary A, Soussi T, Daya-Grosjean L, Sarasin A
Laboratory of Molecular Genetics, Institut de Recherches Scientifiques sur le Cancer, Villejuif, France.
Mutat Res. 1994 May 1;307(1):375-86. doi: 10.1016/0027-5107(94)90311-5.
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.
肿瘤抑制基因p53已被证明是人类癌症中最常发生改变的基因之一。这些改变主要由位于进化保守序列中的点突变组成，这些突变使该蛋白丧失其正常生物学功能的活性。事实上，p53基因存在近300个潜在突变位点，对其进行分析应能使特定突变谱与癌症发展中的不同致病因素相关联。在本研究中，我们分析了正常个体和DNA修复缺陷的着色性干皮病（XP）患者皮肤肿瘤中p53基因的突变谱，并与内部癌症中的突变进行了比较。点突变在皮肤肿瘤中主要是GC→AT转换（非XP患者中为74%，XP患者中为87%），在内部肿瘤中程度较轻（47%），然而在内部肿瘤中，它们主要位于CpG（63%）序列，这可能是由于不稳定的5-甲基胞嘧啶脱氨所致。此外，超过90%的皮肤肿瘤中的突变靶向于嘧啶-嘧啶序列，而内部恶性肿瘤中的突变分布与可变位点处嘧啶-嘧啶位点（61%）和其他序列（39%）的频率成比例。事实上，在XP皮肤肿瘤中，100%的突变靶向于嘧啶-嘧啶序列，其中55%是串联CC→TT转换，被认为是紫外线诱导损伤的特征。在正常个体的皮肤肿瘤中，14%的p53突变是双突变，与XP皮肤肿瘤一样，所有这些都是CC→TT转换。相比之下，内部肿瘤很少含有串联突变（0.8%），其中只有2/14是CC→TT转换。最后，XP中几乎所有（95%）的突变都位于非转录链上，而内部或非XP皮肤肿瘤则没有这种链偏向性。因此，在XP皮肤肿瘤中分析的突变谱也首次证明了人类中存在优先修复。总之，皮肤肿瘤中紫外线诱导的p53突变谱的特异性表明，该基因是将突变谱与特定损伤因素相关联的特别合适的候选基因。
