p53 as a mutagen test in breast cancer
p53 as a mutagen test in breast cancer
复制标题
DOI：
10.1002/em.10065
复制
发表时间：
2002-01-01
影响因子：
2.8
通讯作者：
Sommer, SS
中科院分区：
文献类型：
--
作者：
Hill, KA;Sommer, SS
在大约一半的肿瘤中，p53基因发生了突变。P53基因可用作“突变试验”，即不同类型突变的相对频率可用作流行病学工具，以探讨外源性诱变剂与内源性过程在特定癌症中的作用。P53已被用作乳腺癌的诱变剂检测。令人惊讶的是，在15个地理和种族不同的人群中，p53突变的模式不同。相比之下，人类因子IX基因的突变模式在不同地理和种族的人群中是相似的。乳腺癌中不同的P53突变模式与多种外源诱变剂的显著贡献是一致的。乳房组织对亲脂性诱变剂可能是唯一敏感的，因为它的独特结构，其特征是由易于癌症的乳腺上皮细胞组成的小岛被脂肪细胞的海洋包围。乳腺上皮细胞可能对释放的亲脂诱变剂具有不同的敏感性，这些诱变剂优先集中在邻近的脂肪细胞中，并起源于饮食。为了验证这一假设，我们开发了一种方法来测量乙醇固定的石蜡包埋的人类组织中的突变负载，该方法用抗P53抗体进行免疫组织化学染色。对P53过多阳性的单个细胞进行显微解剖，并对基因进行测序。有可能在正常乳腺组织中识别出高突变负荷的个体，并推测这些个体患乳腺癌的风险更高。此外，采用适当的突变检测方法分析P53基因显著提高了乳腺癌患者早期复发、治疗失败和死亡的预测。诱变剂测试和突变负荷测量是确定诱变剂在乳腺癌中的作用的有用工具。(C)2002年Wiley-Liss，Inc.
The p53 gene is mutated in about half of all tumors. The p53 gene can be used as a "mutagen test," that is, the relative frequencies of the different types of mutation can be used as an epidemiological tool to explore the contribution of exogenous mutagens vs. endogenous processes in particular cancers. p53 has been used as a mutagen test in breast cancer. Surprisingly, the pattern of p53 mutations differs among 15 geographically and ethnically diverse populations. In contrast, mutation patterns in the human factor IX gene are similar in geographically and ethnically diverse populations. Diverse p53 mutation patterns in breast cancer are consistent with a significant contribution by a diversify of exogenous mutagens. Breast tissue may be uniquely sensitive to lipophilic mutagens because of its unique architecture, characterized by tiny islands of cancer-prone mammary epithelial cells surrounded by a sea of adipocytes. Mammary epithelial cells may be differentially susceptible to released lipophilic mutagens preferentially concentrated in adjacent adipocytes and originating in the diet. To test this hypothesis, we developed a method for measuring mutation load from ethanol-fixed, paraffin-embedded human tissues immunohistochemically stained with anti-p53 antibodies. Single cells staining positively for p53 overabundance are microdissected and the gene is sequenced. It is possible to identify individuals with a high mutation load in normal breast tissue and who are presumably at increased risk for breast cancer. In addition, analysis of the p53 gene with appropriate mutation detection methodology markedly improves the prediction of early recurrence, treatment failure, and death in breast cancer patients. Mutagen tests and mutation load measurements are useful tools to identify the role of mutagens in breast cancer. (C) 2002 Wiley-Liss, Inc.