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Science 18 October 1996:
Vol. 274. no. 5286, pp. 430 - 432
DOI: 10.1126/science.274.5286.430
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Reports

Preferential Formation of Benzo[a]pyrene Adducts at Lung Cancer Mutational Hotspots in P53

Mikhail F. Denissenko, Annie Pao, Moon-shong Tang, * Gerd P. Pfeifer *

Cigarette smoke carcinogens such as benzo[a]pyrene are implicated in the development of lung cancer. The distribution of benzo[a]pyrene diol epoxide (BPDE) adducts along exons of the P53 gene in BPDE-treated HeLa cells and bronchial epithelial cells was mapped at nucleotide resolution. Strong and selective adduct formation occurred at guanine positions in codons 157, 248, and 273. These same positions are the major mutational hotspots in human lung cancers. Thus, targeted adduct formation rather than phenotypic selection appears to shape the P53 mutational spectrum in lung cancer. These results provide a direct etiological link between a defined chemical carcinogen and human cancer.

M. F. Denissenko and G. P. Pfeifer, Department of Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
A. Pao and M.-s. Tang, M. D. Anderson Cancer Center, University of Texas, Science Park, Smithville, TX 78957, USA.
*   To whom correspondence should be addressed.

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A. Besaratinia and G. P. Pfeifer (2003)
Cancer Res. 63, 8708-8716
   Abstract »    Full Text »    PDF »
Benzo(a)pyrene Quinones Increase Cell Proliferation, Generate Reactive Oxygen Species, and Transactivate the Epidermal Growth Factor Receptor in Breast Epithelial Cells.
A. D. Burdick, J. W. Davis II, K. J. Liu, L. G. Hudson, H. Shi, M. L. Monske, and S. W. Burchiel (2003)
Cancer Res. 63, 7825-7833
   Abstract »    Full Text »    PDF »
p53 Mutations in Bladder Cancer: Evidence for Exogenous versus Endogenous Risk Factors.
J. C. Schroeder, K. Conway, Y. Li, K. Mistry, D. A. Bell, and J. A. Taylor (2003)
Cancer Res. 63, 7530-7538
   Abstract »    Full Text »    PDF »
P53 alterations in bladder tumors from arsenic and tobacco exposed patients.
L. E. Moore, A. H. Smith, C. Eng, S. DeVries, D. Kalman, V. Bhargava, K. Chew, C. Ferreccio, O. A. Rey, C. Hopenhayn, et al. (2003)
Carcinogenesis 24, 1785-1791
   Abstract »    Full Text »    PDF »
Position-specific trapping of topoisomerase II by benzo[a]pyrene diol epoxide adducts: Implications for interactions with intercalating anticancer agents.
Q. A. Khan, G. Kohlhagen, R. Marshall, C. A. Austin, G. P. Kalena, H. Kroth, J. M. Sayer, D. M. Jerina, and Y. Pommier (2003)
PNAS 100, 12498-12503
   Abstract »    Full Text »    PDF »
Association of the DNA repair gene XPD Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer.
W.-M. Gao, M. Romkes, R. D. Day, J. M. Siegfried, J. D. Luketich, H. H. Mady, M. F. Melhem, and P. Keohavong (2003)
Carcinogenesis 24, 1671-1676
   Abstract »    Full Text »    PDF »
Australia's National Tobacco Campaign.
D Hill and T Carroll (2003)
Tob. Control 12, ii9-14
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The p53-dependent effects of macrophage migration inhibitory factor revealed by gene targeting.
G. Fingerle-Rowson, O. Petrenko, C. N. Metz, T. G. Forsthuber, R. Mitchell, R. Huss, U. Moll, W. Muller, and R. Bucala (2003)
PNAS 100, 9354-9359
   Abstract »    Full Text »    PDF »
Screening of Homologous Recombination Gene Polymorphisms in Lung Cancer Patients Reveals an Association of the NBS1-185Gln Variant and p53 Gene Mutations.
P. P. Medina, S. A. Ahrendt, M. Pollan, P. Fernandez, D. Sidransky, and M. Sanchez-Cespedes (2003)
Cancer Epidemiol. Biomarkers Prev. 12, 699-704
   Abstract »    Full Text »    PDF »
Tobacco Smoke-induced Lung Cell Proliferation Mediated by Tumor Necrosis Factor {alpha}-converting Enzyme and Amphiregulin.
H. Lemjabbar, D. Li, M. Gallup, S. Sidhu, E. Drori, and C. Basbaum (2003)
J. Biol. Chem. 278, 26202-26207
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p53 Mutations and Survival in Stage I Non-Small-Cell Lung Cancer: Results of a Prospective Study.
S. A. Ahrendt, Y. Hu, M. Buta, M. P. McDermott, N. Benoit, S. C. Yang, L. Wu, and D. Sidransky (2003)
J Natl Cancer Inst 95, 961-970
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Curcumin (diferuloylmethane) down-regulates cigarette smoke-induced NF-{kappa}B activation through inhibition of I{kappa}B{alpha} kinase in human lung epithelial cells: correlation with suppression of COX-2, MMP-9 and cyclin D1.
S. Shishodia, P. Potdar, C. G. Gairola, and B. B. Aggarwal (2003)
Carcinogenesis 24, 1269-1279
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Folate status, metabolic genotype, and biomarkers of genotoxicity in healthy subjects.
A. Zijno, C. Andreoli, P. Leopardi, F. Marcon, S. Rossi, S. Caiola, A. Verdina, R. Galati, A. Cafolla, and R. Crebelli (2003)
Carcinogenesis 24, 1097-1103
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