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ALTERNATE PATHWAY TO LUNG CANCER INDICATED BY KRAS AND P53 MUTATIONS IN NONSMOKERS EXPOSED TO INDOOR SMOKY COAL EMISSIONS
Citation:
DeMarini, D M., S Landi, D. Tian, N. M. Hanley, W. Gao, P. Keohavong, AND J L. Mumford. ALTERNATE PATHWAY TO LUNG CANCER INDICATED BY KRAS AND P53 MUTATIONS IN NONSMOKERS EXPOSED TO INDOOR SMOKY COAL EMISSIONS. Presented at Environmental Mutagen Society, San Diego, California, March 16-21, 2001.
Description:
Alternate Pathway to Lung Cancer Indicated by KRAS and P53 Mutations in Nonsmokers Exposed to Indoor Smoky Coal 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 P53 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 P53 mutation spectra in adenocarcinoma lung tumors from 24 women from this uniquely exposed population of nonsmokers, including 13 cases of bronchioloalveolar carcinomas and 11 cases of acinar adenocarcinomas. At codon 12 of KRAS, 29% of the tumors were KRAS + , with 86% ( 617) being G to T. Immunohistochemical staining for P53 protein revealed that 88% of the tumors had >50% of their cells showing P53+. DNA sequence analysis ofexons 4-9 showed that 71% of the tumors contained P53 mutations, with 17% having 2 P53 mutations each; 21% had both KRASand P53 mutations. The majority of the mutations in P53 were G to T transversions (86%), followed by G to A (10%). One third of the mutations occurred within codons 153-158, which is a GC-rich region, and 100% of all of the mutated Gs were on the coding strand. This is the highest percentage of G to T mutations ever recorded at either gene; the highest percentage of mutations recorded at codons 153-158 in the P53 gene, and the most extreme strand bias ever observed in the P53 gene. This unusual mutation spectrum in smoky coal-exposed subjects is consistent with external exposure to polycyclic aromatic hydrocarbons (PAHs ), which is the primary component of smoky coal emissions. Such data support the view that the mutagenic PAHs in the smoky coal induced the observed mutations, resulting in this unique mutation pathway to lung cancer in this nonsmoking population. These results indicate that mutations in the P53 gene can reflect a specific environmental exposure.
Abstract does not necessarily represent the policy of the US EPA.