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Type of TP53 mutation influences oncogenic potential and spectrum of associated K-ras mutations in lung-specific transgenic mice.
- Source :
-
International journal of cancer [Int J Cancer] 2019 Nov 01; Vol. 145 (9), pp. 2418-2426. Date of Electronic Publication: 2019 Apr 13. - Publication Year :
- 2019
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Abstract
- TP53 and K-ras mutations are two of the major genetic alterations in human nonsmall cell lung cancers. The association between these two genes during lung tumorigenesis is unknown. We evaluated the potential of two common Type I (273H, contact) and Type II (175H, conformational) TP53 mutations to induce lung tumors in transgenic mice, as well as K-ras status, and other driver mutations in these tumors. Among 516 (138 nontransgenic, 207 SPC-TP53-273H, 171 SPC-TP53-175H) mice analyzed, 91 tumors, all adenocarcinomas, were observed. Type II mutants developed tumors more frequently (as compared to nontransgenics, p = 0.0003; and Type I, p = 0.010), and had an earlier tumor onset compared to Type I (p = 0.012). K-ras mutations occurred in 21 of 50 (42%) of murine lung tumors sequenced. For both the nontransgenic and the SPC-TP53-273H transgenics, tumor K-ras codon 12-13 mutations occurred after 13 months with a peak incidence at 16-18 months. However, for the SPC-TP53-175H transgenics, K-ras codon 12-13 mutations were observed as early as 6 months, with a peak incidence between the ages of 10-12 months. Codons 12-13 transversion mutations were the predominant changes in the SPC-TP53-175H transgenics, whereas codon 61 transition mutations were more common in the SPC-TP53-273H transgenics. The observation of accelerated tumor onset, early appearance and high frequency of K-ras codon 12-13 mutations in the Type II TP53-175H mice suggests an enhanced oncogenic function of conformational TP53 mutations, and gains in early genetic instability for tumors containing these mutations compared to contact mutations.<br /> (© 2019 UICC.)
- Subjects :
- Adenocarcinoma of Lung genetics
Adenocarcinoma of Lung metabolism
Age of Onset
Animals
Female
Humans
Lung Neoplasms genetics
Lung Neoplasms metabolism
Male
Mice
Mice, Transgenic
Protein Conformation
Sequence Analysis, DNA
Tumor Suppressor Protein p53 chemistry
Tumor Suppressor Protein p53 metabolism
Adenocarcinoma of Lung pathology
Lung Neoplasms pathology
Mutation
Proto-Oncogene Proteins p21(ras) genetics
Tumor Suppressor Protein p53 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0215
- Volume :
- 145
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 30873587
- Full Text :
- https://doi.org/10.1002/ijc.32279