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LUNG TUMOR KRAS AND TP53 MUTATIONS IN NONSMOKERS REFLECT EXPOSURE TO PAH-RICH COAL COMBUSTION EMISSIONS
Citation:
DeMarini, D M., S Landi, D. Tian, N. M. Hanley, B C. Roop, P. Keohavong, W. Gao, M. Olivier, P. Hainaut, AND J L. Mumford. LUNG TUMOR KRAS AND TP53 MUTATIONS IN NONSMOKERS REFLECT EXPOSURE TO PAH-RICH COAL COMBUSTION EMISSIONS. Presented at ISEA/ISEE Symposium, Vancouver, BC Canada, 08/11-15/2002.
Description:
Lung Tumor KRAS and TP53 Mutations in Nonsmokers Reflect Exposure to PAH-Rich
Coal Combustion Emissions
Use of smoky coal in unvented homes in Xuan Wei County, Yunnan Province, China, is associated with lung cancer among nonsmoking females. Such women have the highest lung cancer rate in China--8X the national average for females. Although the KRAS and TP 53 mutation spectra in lung tumors of smokers are well characterized, the corresponding data base for nonsmokers is small, and no such data have been generated for nonsmokers whose lung cancer is clearly linked epidemiologically to an environmental exposure other than tobacco smoke. Thus, we have examined the KRAS and TP53 mutation spectra in adenocarcinoma ltmg tumors from 24 women from this uniquely exposed population of nonsmokers, which included 13 cases of bronchioloalveolar adenocarcinomas and 11 cases of acinar adenocarcinomas. At codon 12 ofKRA.), 29% of the tumors were KRAS+, with 86% (6/7) being G > T transversions. Immunohistochemical staining for TP53 protein revealed that 88% of the tumors had ? 50% of their cells stain TP53+ .DNA sequence analysis of exons 4-9 showed that 71% of the tumors contained TP 53 mutations, with 17% having 2 TP 53 mutations each; 21% had both KRAS and TP53 mutations. The majority (76%) of the mutations in TP53 were G > T transversions. One third of the mutations occurred within codons 153-158, which is a GC-rich region, and 100% of all of the mutated Gs of the G > T mutations were on the coding strand. This is the highest percentage of (a) G > T mutations ever recorded at either gene, (b) mutations recorded at codons 153-158, and (c) strand bias ever observed. This tmusual mutation spectrum is consistent with external exposure to polycyclic aromatic hydrocarbons (P AHs ), which are the primary component of smoky coal emissions. Such data support the view that mutations in the TP53 gene can reflect a specific environmental exposure.
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