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Point mutations in normal lungs of smokers and non-smokers

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dc.contributor.advisor William G. Thilly. en_US
dc.contributor.author Sudo, Hiroko, 1977- en_US
dc.contributor.other Massachusetts Institute of Technology. Biological Engineering Division. en_US
dc.date.accessioned 2007-02-22T15:55:19Z
dc.date.available 2007-02-22T15:55:19Z
dc.date.copyright 2004 en_US
dc.date.issued 2004 en_US
dc.identifier.uri http://hdl.handle.net/1721.1/36321
dc.description Thesis (Ph. D. in Genetic Toxicology)--Massachusetts Institute of Technology, Biological Engineering Division, 2004. en_US
dc.description This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections. en_US
dc.description Includes bibliographical references (p. 139-161). en_US
dc.description.abstract It is a widely-held hypothesis that environmental mutagens play an essential role in human somatic and germinal cell mutagenesis. In particular, the finding of small amounts of chemical mutagens in cigarette smoke has led to the general hypothesis that mutagens in cigarette smoke induce oncomutations and thus account for the carcinogenic effect of cigarette smoking in human lungs. However, this hypothesis has not been tested by an assay of nuclear point mutations in lungs of smokers and nonsmokers. Mismatch amplification mutation assay (MAMA), an effective form of allele-specific PCR, was applied for detection of point mutations in TP53 bp742, bp746 and bp747, K-ras bp35 and HPRT bp508 from a total of 291 tracheal-bronchial epithelial sectors from six smokers and nine non-smokers, yielding 949 individual mutational assays. The conditions of MAMA for each target point mutations were optimized such that the sensitivity of each was equal to or below 10⁻⁵. Lung epithelial sectors of 2.3x10⁶ cells in average contained 0-200 mutant cells in general, equivalent to mutant fractions (MFs) of 0-10⁻⁴ with an exception of rare sectors with MF larger than 4x 10⁻⁴ (4.6%). Noticeably, the distributions of the MFs among sectors did not vary appreciably with the donor's smoking status. The mean MFs per lung were very similar between smokers and non-smokers for all five target mutations assayed (p >> 0.05). The mean MFs were slightly higher in females than males (p = 0.015). The mean MFs increased with age of the subjects although the correlation did not reach statistical significance due to large variances within the same age group. The distributions of MF among sectors of smokers and non-smokers did not differ significantly by Kolmogorov-Smirnov test en_US
dc.description.abstract (cont.) for all target mutations but HPRT. By using hypothetical turnover unit sizes and Poisson distribution, the turnover unit size of human tracheal bronchial epithelium was estimated as 64 cells (p = 0.05). These observations do not support the widely-held hypothesis that cigarette smoking causes lung cancer through its induction of point mutations in nuclear genes. The current findings demonstrate the necessity of investigation on alternative mechanisms for tobacco smoke in lung carcinogenesis. en_US
dc.description.statementofresponsibility by Hiroko Sudo. en_US
dc.format.extent 194 p. en_US
dc.language.iso eng en_US
dc.publisher Massachusetts Institute of Technology en_US
dc.rights M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. en_US
dc.rights.uri http://dspace.mit.edu/handle/1721.1/7582
dc.subject Biological Engineering Division. en_US
dc.title Point mutations in normal lungs of smokers and non-smokers en_US
dc.type Thesis en_US
dc.description.degree Ph.D.in Genetic Toxicology en_US
dc.contributor.department Massachusetts Institute of Technology. Biological Engineering Division. en_US
dc.identifier.oclc 55590318 en_US


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