This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yoon, J.-H. Articles by Pfeifer, G. P. Search for Related Content PubMed PubMed Citation Articles by Yoon, J.-H. Articles by Pfeifer, G. P.

Methylated CpG Dinucleotides Are the Preferential Targets for G-to-T Transversion Mutations Induced by Benzo[a]pyrene Diol Epoxide in Mammalian Cells

Similarities with the p53 Mutation Spectrum in Smoking-associated Lung Cancers¹

Department of Biology, Beckman Research Institute of the City of Hope, Duarte, California 91010 [J-H. Y., L. E. S., G. P. P.]; Department of Biochemistry, College of Natural Sciences, Yeungnam University, Kyongsan, 712-749 Korea [J-H. Y., C-S. L.]; and New York University, Department of Environmental Medicine, Tuxedo, New York 10987 [Z. F., M-s. T.]

A large fraction of the p53 mutations in lung cancers from smokers are G-to-T transversions, a type of mutation that is infrequent in lung cancers from nonsmokers and in most other tumors. Previous studies have indicated that there is an association between G-to-T transversion hotspots in lung cancers and sites of preferential formation of polycyclic aromatic hydrocarbon adducts along the p53 gene. p53 codons containing methylated CpG sequences are preferential targets for formation of adducts by (±) anti-7ß,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE). To assess the role of CpG methylation in induction of mutations by BPDE, we analyzed BPDE mutagenesis in three CpG methylated target genes: a supF shuttle vector and the cII and lacI transgenes in embryonic mouse fibroblasts. After methylation of the shuttle vector at all CpG sequences, 42% of all G-to-T transversions were at CpG sites compared with 23% in unmethylated DNA. In the cII transgene, which is methylated at CpG sequences in vivo, 83 of 147 (56%) of the BPDE-induced mutations were G-to-T transversions, and 58% (48 of 83) of all G-to-T transversions occurred at methylated CpG sequences. In the lacI gene, 68% (75 of 111) of the BPDE-induced mutations were G-to-T events, and 58 of 75 (77%) of these occurred at methylated CpG sequences. The occurrence of transversion hotspots at methylated CpGs correlated with high levels of BPDE adducts formed at such sites. This situation mirrors the one in the p53 gene in lung cancers from smokers where 236 of 465 (51%) of the G-to-T transversions occurred at methylated CpG sites. These findings further strengthen a link between polycyclic aromatic hydrocarbons present in cigarette smoke and lung cancer mutations and provide evidence that mutational processes other than C-to-T transition mutations can occur selectively at methylated CpG sequences.

This article has been cited by other articles:

				B. J. Evison, R. A. Bilardi, F. C. K. Chiu, G. Pezzoni, D. R. Phillips, and S. M. Cutts CpG methylation potentiates pixantrone and doxorubicin-induced DNA damage and is a marker of drug sensitivity Nucleic Acids Res., October 1, 2009; 37(19): 6355 - 6370. [Abstract] [Full Text] [PDF]

				T. Vaissiere, R. J. Hung, D. Zaridze, A. Moukeria, C. Cuenin, V. Fasolo, G. Ferro, A. Paliwal, P. Hainaut, P. Brennan, et al. Quantitative Analysis of DNA Methylation Profiles in Lung Cancer Identifies Aberrant DNA Methylation of Specific Genes and Its Association with Gender and Cancer Risk Factors Cancer Res., January 1, 2009; 69(1): 243 - 252. [Abstract] [Full Text] [PDF]

				A. Besaratinia, S.-i. Kim, and G. P. Pfeifer Rapid repair of UVA-induced oxidized purines and persistence of UVB-induced dipyrimidine lesions determine the mutagenicity of sunlight in mouse cells FASEB J, July 1, 2008; 22(7): 2379 - 2392. [Abstract] [Full Text] [PDF]

				B. Sadikovic, J. Andrews, D. Carter, J. Robinson, and D. I. Rodenhiser Genome-wide H3K9 Histone Acetylation Profiles Are Altered in Benzopyrene-treated MCF7 Breast Cancer Cells J. Biol. Chem., February 15, 2008; 283(7): 4051 - 4060. [Abstract] [Full Text] [PDF]

				D. A. Delker, D. R. Geter, K. M. Kleinert, and B. B. Gollapudi Frequency and Spectrum of lacI Mutations in the Liver of Big Blue Mice Following the Administration of Genotoxic Carcinogens Singly and in Series International Journal of Toxicology, January 1, 2008; 27(1): 35 - 42. [Abstract] [Full Text] [PDF]

				Z. Herceg Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors Mutagenesis, March 1, 2007; 22(2): 91 - 103. [Abstract] [Full Text] [PDF]

				M. C. Shin, S. J. Lee, J. E. Choi, S. I. Cha, C. H. Kim, W. K. Lee, S. Kam, Y. M. Kang, T. H. Jung, and J. Y. Park Glu346Lys Polymorphism in the Methyl-CpG Binding Domain 4 Gene and the Risk of Primary Lung Cancer Jpn. J. Clin. Oncol., August 1, 2006; 36(8): 483 - 488. [Abstract] [Full Text] [PDF]

				A. Besaratinia and G. P. Pfeifer Investigating human cancer etiology by DNA lesion footprinting and mutagenicity analysis Carcinogenesis, August 1, 2006; 27(8): 1526 - 1537. [Abstract] [Full Text] [PDF]

				J.-S. Jang, S. J. Lee, J. E. Choi, S. I. Cha, E. B. Lee, T. I. Park, C. H. Kim, W. K. Lee, S. Kam, J.-Y. Choi, et al. Methyl-CpG Binding Domain 1 Gene Polymorphisms and Risk of Primary Lung Cancer Cancer Epidemiol. Biomarkers Prev., November 1, 2005; 14(11): 2474 - 2480. [Abstract] [Full Text] [PDF]

				K. K. Alharbi, M. A. Aldahmesh, E. Spanakis, L. Haddad, R. A. Whittall, X.-h. Chen, H. Rassoulian, M. J. Smith, J. Sillibourne, N. J. Ball, et al. Mutation scanning by meltMADGE: Validations using BRCA1 and LDLR, and demonstration of the potential to identify severe, moderate, silent, rare, and paucimorphic mutations in the general population Genome Res., July 1, 2005; 15(7): 967 - 977. [Abstract] [Full Text] [PDF]

				F. Le Calvez, A. Mukeria, J. D. Hunt, O. Kelm, R. J. Hung, P. Taniere, P. Brennan, P. Boffetta, D. G. Zaridze, and P. Hainaut TP53 and KRAS Mutation Load and Types in Lung Cancers in Relation to Tobacco Smoke: Distinct Patterns in Never, Former, and Current Smokers Cancer Res., June 15, 2005; 65(12): 5076 - 5083. [Abstract] [Full Text] [PDF]

				S. J. Lee, H.-S. Jeon, J.-S. Jang, S. H. Park, G. Y. Lee, B.-H. Lee, C. H. Kim, Y. M. Kang, W. K. Lee, S. Kam, et al. DNMT3B polymorphisms and risk of primary lung cancer Carcinogenesis, February 1, 2005; 26(2): 403 - 409. [Abstract] [Full Text] [PDF]

				J.-H. Yoon, A. Besaratinia, Z. Feng, M.-s. Tang, S. Amin, A. Luch, and G. P. Pfeifer DNA Damage, Repair, and Mutation Induction by (+)-Syn and (-)-Anti-Dibenzo[a,l]Pyrene-11,12-Diol-13,14-Epoxides in Mouse Cells Cancer Res., October 15, 2004; 64(20): 7321 - 7328. [Abstract] [Full Text] [PDF]

				P. D. Lewis and J. M. Parry In silico p53 mutation hotspots in lung cancer Carcinogenesis, July 1, 2004; 25(7): 1099 - 1107. [Abstract] [Full Text] [PDF]

				J. G. Valadez and F. P. Guengerich S-(2-Chloroethyl)glutathione-generated p53 Mutation Spectra Are Influenced by Differential Repair Rates More than Sites of Initial DNA Damage J. Biol. Chem., April 2, 2004; 279(14): 13435 - 13446. [Abstract] [Full Text] [PDF]

				A. Besaratinia and G. P. Pfeifer Enhancement of the Mutagenicity of Benzo(a)pyrene Diol Epoxide by a Nonmutagenic Dose of Ultraviolet A Radiation Cancer Res., December 15, 2003; 63(24): 8708 - 8716. [Abstract] [Full Text] [PDF]

				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. P53 alterations in bladder tumors from arsenic and tobacco exposed patients Carcinogenesis, November 1, 2003; 24(11): 1785 - 1791. [Abstract] [Full Text] [PDF]

				J.-H. Yoon, C.-S. Lee, and G. P. Pfeifer Simulated sunlight and benzo[a]pyrene diol epoxide induced mutagenesis in the human p53 gene evaluated by the yeast functional assay: lack of correspondence to tumor mutation spectra Carcinogenesis, January 1, 2003; 24(1): 113 - 119. [Abstract] [Full Text] [PDF]

				A. Besaratinia, S. E. Bates, and G. P. Pfeifer Mutational Signature of the Proximate Bladder Carcinogen N-Hydroxy-4-acetylaminobiphenyl: Inconsistency with the p53 Mutational Spectrum in Bladder Cancer Cancer Res., August 1, 2002; 62(15): 4331 - 4338. [Abstract] [Full Text] [PDF]

				A. Besaratinia, L.M. Maas, E.M.C. Brouwer, E.J.C. Moonen, T.M.C.M. De Kok, G.J. Wesseling, S. Loft, J.C.S. Kleinjans, and F.J. Van Schooten A molecular dosimetry approach to assess human exposure to environmental tobacco smoke in pubs Carcinogenesis, July 1, 2002; 23(7): 1171 - 1176. [Abstract] [Full Text] [PDF]