Daya-Grosjean L, Dumaz N, Sarasin A
Laboratory of Molecular Genetics, Institut de Recherche sur le Cancer (IFC 1), Villejuif, France.
J Photochem Photobiol B. 1995 May;28(2):115-24. doi: 10.1016/1011-1344(95)07130-t.
Ultraviolet (UV) irradiation emitted by the sun has been clearly implicated as a major carcinogen in the formation of skin cancers in man. Indeed, the high levels of cutaneous tumors in xeroderma pigmentosum patients (XP) who are deficient in repair of UV-induced lesions have confirmed that DNA damage produced by sunlight is directly involved in the cancer development. The tumor suppressor gene, p53, very frequently found modified in human cancers, has proved to be a perfect target gene for correlating mutation spectra with different cancer causing agents as there are nearly 300 potential mutation sites available for analysis. In a comparative analysis of p53 mutations found in internal cancers with those in skin tumours we show here that clear differences exist between the types of spectra obtained. The specificity of UV induced mutations in skin cancers is confirmed when single and tandem mutations are compared. Most of the p53 point mutations found are GC to AT transitions both in skin and internal tumors where in the latter they are located mainly at CpG sequences probably due to the deamination of the unstable 5-MeC. Moreover, mutations are targeted at py-py sequences in over 90% of skin tumors whereas in internal cancers the distribution is proportional to the frequency of bipyrimidine sequences in the p53 gene. Most significantly, all mutations found in XP skin tumors are targeted at py-py sites and more than 50% are tandem CC to TT transitions considered as veritable signatures of UV-induced lesions. Tandem mutations are also relatively common (14%) in skin tumors from normal individuals compared to their very rare occurrence in internal malignancies (0.8%). Finally, nearly all mutations observed in XP skin tumors are due to unrepaired lesions remaining on the coding strand whereas no strand bias is seen in mutation location of internal or skin tumors from normal individuals. In fact the mutation spectrum analysed in XP skin cancers has permitted the first demonstration of the existence of preferential repair in man. In conclusion, using the p53 gene as a probe it is obvious that the mutation spectra from skin tumors are very similar to those observed in UV-treated gene targets in model systems but statistically different from those described in other types of human cancer. This has allowed us to demonstrate, without ambiguity, the major role of UV-induced DNA lesions in sunlight related skin carcinogenesis.
太阳发出的紫外线（UV）辐射已被明确认定为人类皮肤癌形成的主要致癌物。事实上，着色性干皮病患者（XP）因缺乏修复紫外线诱导损伤的能力，其皮肤肿瘤高发，这证实了阳光产生的DNA损伤直接参与癌症发展。肿瘤抑制基因p53在人类癌症中经常被发现发生改变，由于有近300个潜在突变位点可供分析，它已被证明是将突变谱与不同致癌剂相关联的理想靶基因。在对内部癌症和皮肤肿瘤中发现的p53突变进行的比较分析中，我们在此表明所获得的谱型之间存在明显差异。当比较单突变和串联突变时，紫外线诱导皮肤癌突变的特异性得到证实。在皮肤和内部肿瘤中发现的大多数p53点突变都是从GC到AT的转换，在后者中它们主要位于CpG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嘧啶-嘧啶序列，而在内部癌症中，分布与p53基因中双嘧啶序列的频率成比例。最显著的是，在XP皮肤肿瘤中发现的所有突变都靶向嘧啶-嘧啶位点，超过50%是串联的CC到TT转换，这被认为是紫外线诱导损伤的真正特征。与在内部恶性肿瘤中非常罕见的情况（0.8%）相比，串联突变在正常个体的皮肤肿瘤中也相对常见（14%）。最后，在XP皮肤肿瘤中观察到的几乎所有突变都是由于编码链上残留的未修复损伤，而在正常个体的内部或皮肤肿瘤的突变位置中未观察到链偏向。事实上，对XP皮肤癌中分析的突变谱的研究首次证明了人类中存在优先修复现象。总之，以p53基因为探针，很明显皮肤肿瘤的突变谱与模型系统中紫外线处理的基因靶标中观察到的非常相似，但在统计学上与其他类型人类癌症中描述的不同。这使我们能够明确证明紫外线诱导的DNA损伤在与阳光相关的皮肤致癌作用中的主要作用。
