期刊
ENVIRONMENTAL AND MOLECULAR MUTAGENESIS
卷 39, 期 2-3, 页码 216-227出版社
WILEY-LISS
DOI: 10.1002/em.10065
关键词
p53 gene; environmental mutagens; endogenous processes; spontaneous mutations; mutagen test; mutation pattern; mutation load; mutation scanning; genetic predisposition
资金
- NHLBI NIH HHS [HL39762] Funding Source: Medline
- NINDS NIH HHS [NS33354] Funding Source: Medline
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL039762] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS033354] Funding Source: NIH RePORTER
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.
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