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p53 Gene Mutations in SKH‐1 Mouse Tumors Differentially Induced by UVB and Combined Subcarcinogenic Benzo[a]pyrene and UVA †
Author(s) -
Wang Yongyin,
Zhou Xueyan,
Weinstein Elhav,
Maryles Billie,
Zhang Yanzhen,
Moore Julian,
Gao Dayuan,
Atencio David P.,
Rosenstein Barry S.,
Lebwohl Mark,
Chen HongDuo,
Xiao Ting,
Wei Huachen
Publication year - 2008
Publication title -
photochemistry and photobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 131
eISSN - 1751-1097
pISSN - 0031-8655
DOI - 10.1111/j.1751-1097.2007.00282.x
Subject(s) - exon , microbiology and biotechnology , missense mutation , mutation frequency , mutation , gene mutation , gene , cancer research , biology , chemistry , genetics
We compared the frequency and spectra of p53 mutations in skin tumors from UVB‐irradiated and benzo(a)pyrene‐UVA‐treated SKH‐1 mice. Analysis of p53 mutations using a combination of polymerase chain reaction, denaturing high‐performance liquid chromatography, and sequencing shows that the frequency and spectrum of p53 mutations in BaP‐UVA‐induced tumors are quite different from those in UVB‐induced tumors. SKH‐1 mice were treated with BaP‐UVA or UVB for 30 weeks after which skin tumors were collected for analysis of p53 mutations. Among the 11 BaP‐UVA‐induced tumors with diameters of 5–10 mm, two displayed mutations in exon 8 yielding a mutation frequency of 18.2%. In contrast, the mutation frequency among BaP‐UVA‐induced tumors was 10.5%. In UVB‐induced tumors, the mutation frequency in exon 8 was highly correlated with tumor size. A total of 77.8% of tumors with diameters larger than 10 mm contained p53 mutations. The overall mutation frequency among UVB‐induced tumors was 17.9% in exon 8 and only 3.8% in exon 5. Hotspots for p53 mutation in UVB‐induced tumors were found at codons 128 and 149 (exon 5), and at codons 268, 270, 271 and 273–276 (exon 8). In addition to widely recognized C→T missense mutations, there were also tandem CC→AG changes coupled with either an insertion of T, a C→G substitution or G→C/T mutations. All of the mutations were found at tri‐ or tetra‐pyrimidine sites. Thirty‐nine per cent of all p53 mutations occurred at codons 274 and 275; 53% occurred at codons 268–271. Two multiple mutation clusters were located at codons 268–271 and 274–276. Both BaP‐UVA and UVB caused C→T transitions at codon 275 in exon 8. A C→T mutation at codon 294 was induced only by BaP‐UVA treatment. In contrast to UVB treatment, BaP‐UVA treatment did not induce any mutations in exon 5. We show that individually subcarcinogenic levels of BaP and UVA synergistically induce a novel p53 ‐mutation fingerprint. This fingerprint could serve as a prognostic indicator for the development of BaP‐UVA‐induced skin tumors.