MUTATION HOTSPOTS DUE TO SUNLIGHT IN THE P53 GENE OF NONMELANOMA SKIN CANCERS
MUTATION HOTSPOTS DUE TO SUNLIGHT IN THE P53 GENE OF NONMELANOMA SKIN CANCERS
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DOI：
10.1073/pnas.90.9.4216
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发表时间：
1993-05-01
影响因子：
11.1
通讯作者：
BRASH, DE
中科院分区：
文献类型：
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作者：
ZIEGLER, A;LEFFELL, DJ;BRASH, DE
为了确定p53肿瘤抑制基因中最易受日光致癌突变的位点，对27例皮肤基底细胞癌（BCCs）的整个编码区进行了测序。56%的肿瘤含有突变，这些是紫外线样的：主要是CC - b>tt或C - b>t在双嘧啶位点的变化。这种突变可以改变p53中393个氨基酸中的一半以上，但三分之二发生在9个位点，这些位点的突变在BCC或27个先前研究过的皮肤鳞状细胞癌中不止一次出现。这些突变热点中有7个是皮肤癌特有的。非双嘧啶位点的内部癌症热点在皮肤癌中没有突变；此外，这些核苷酸上没有紫外线光产物。与其他癌症相比，热点的存在改变了BCC中p53失活的过程：等位基因丢失很罕见，但45%的点突变伴随着另一个等位基因的第二个点突变。每对中至少有一个位于热点。在突变热点处起作用的阳光似乎频繁地引起突变，以至于它经常导致BCC发育中的两个遗传事件。
To identify the sites in the p53 tumor suppressor gene most susceptible to carcinogenic mutation by sunlight, the entire coding region of 27 basal cell carcinomas (BCCs) of the skin was sequenced. Fifty-six percent of tumors contained mutations, and these were UV-like: primarily CC --> TT or C --> T changes at dipyrimidine sites. Such mutations can alter more than half of the 393 amino acids in p53, but two-thirds occurred at nine sites at which mutations were seen more than once in BCC or in 27 previously studied squamous cell carcinomas of the skin. Seven of these mutation hotspots were specific to skin cancers. Internal-cancer hotspots not located at dipyrimidine sites were not mutated in skin cancers; moreover, UV photoproducts were absent at these nucleotides. The existence of hotspots altered the process of inactivating p53 in BCC compared to other cancers: allelic loss was rare, but 45% of the point mutations were accompanied by a second point mutation on the other allele. At least one of each pair was located at a hotspot. Sunlight, acting at mutation hotspots, appears to cause mutations so frequently that it is often responsible for two genetic events in BCC development.