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dc.contributor.authorHussain, SPen_US
dc.contributor.authorAmstad, Pen_US
dc.contributor.authorRaja, Ken_US
dc.contributor.authorSawyer, Men_US
dc.contributor.authorHofseth, Len_US
dc.contributor.authorShields, PGen_US
dc.contributor.authorHewer, Aen_US
dc.contributor.authorPhillips, DHen_US
dc.contributor.authorRyberg, Den_US
dc.contributor.authorHaugen, Aen_US
dc.contributor.authorHarriss, CCen_US
dc.date.accessioned2018-09-24T15:50:32Z
dc.date.issued2001-09-01en_US
dc.identifier17en_US
dc.identifier.citationCANCER RESEARCH, 2001, 61 pp. 6350 - 6355en_US
dc.identifier.issn0008-5472en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2823
dc.description.abstractp53 mutations are common in lung cancer. In smoking-associated lung cancer, the occurrence of G:C to TA transversions at hotspot codons, e.g., 157, 248, 249, and 273, has been linked to the presence of carcinogenic chemicals in tobacco smoke including polycyclic aromatic hydrocarbons such as benzo(a)pyrene (BP). In the present study, we have used a highly sensitive mutation assay to determine the p53 mutation load in nontumorous human lung and to study the mutability of p53 codons 157, 248, 249, and 250 to benzo(a)pyrene-diol-epoxide (BPDE), an active metabolite of BP in human bronchial epithelial BEAS-2B cells. We determined the p53 mutational load at codons 157, 248, 249, and 250 in nontumorous peripheral lung tissue either from lung cancer cases among smokers or noncancer controls among smokers and nonsmokers. A 5-25-fold higher frequency of GTC(val) to TTCphe transversions at codon 157 was found in nontumorous samples (57%) from cancer cases (n = 14) when compared with noncancer controls (n = 8; P < 0.01). Fifty percent (7/14) of the nontumorous samples from lung cancer cases showed a high frequency of codon 249 AGG(arg) to AGT(ser) mutations (P < 0.02). Four of these seven samples with AGT(ser) mutations also showed a high frequency of codon 249 AGG(arg) to ATG(met) mutations, whereas only one sample showed a codon 250 CCC to ACC transversion. Tumor tissue from these lung cancer cases (38%) contained p53 mutations but were different from the above mutations found in the nontumorous pair. Noncancer control samples from smokers or nonsmokers did not contain any detectable mutations at codons 248, 249, or 250. BEAS-2B bronchial epithelial cells exposed to doses of 0.125, 0.5, and 1.0 muM BPDE, showed G:C to T:A transversions at codon 157 at a frequency of 3.5 x 10(-7), 4.4 x 10(-7), and 8.9 x 10(-7), respectively. No mutations at codon 157 were found in the DMSO-treated controls. These doses of BPDE induced higher frequencies, ranging from 4-12-fold, of G:C to TA transversions at codon 248, G:C to T:A transversions and G:C to A:T transitions at codon 249, and C;G to TA transitions at codon 250 when compared with the DMSO-treated controls. These data are consistent with the hypothesis that chemical carcinogens such as BP in cigarette smoke cause G:C to T:A transversions at p53 codons 157, 248, and 249 and that nontumorous lung tissues from smokers with lung cancer carry a high p53 mutational load at these codons.en_US
dc.format.extent6350 - 6355en_US
dc.titleMutability of p53 hotspot codons to benzo(a)pyrene diol epoxide (BPDE) and the frequency of p53 mutations in nontumorous human lungen_US
dc.typeJournal Article
rioxxterms.licenseref.startdate2001-09-01en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfCANCER RESEARCHen_US
pubs.notesresearcherid-numbers: Shields, Peter/I-1644-2012 unique-id: ISI:000170637700009en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Human Biomonitoring & Carcinogen Activation
pubs.volume61en_US
pubs.embargo.termsNot knownen_US
icr.researchteamHuman Biomonitoring & Carcinogen Activationen_US
dc.contributor.icrauthorPhillips, David Hunteren_US
dc.contributor.icrauthorHewer, Alanen_US


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