Type of TP53 mutation influences oncogenic potential and spectrum of associated K‐ras mutations in lung‐specific transgenic mice

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 in...

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Published in:International journal of cancer 2019-11, Vol.145 (9), p.2418-2426
Main Authors: Duan, Wenrui, Gao, Li, Kalvala, Arjun, Aguila, Brittany, Brooks, Christopher, Mo, Xiaokui, Ding, Haiming, Shilo, Konstantin, Otterson, Gregory A., Villalona‐Calero, Miguel A.
Format: Article
Language:English
Subjects:
Adenocarcinoma of Lung - genetics
Adenocarcinoma of Lung - metabolism
Adenocarcinoma of Lung - pathology
Age of Onset
Animals
Cancer
Codons
Female
gains of function
Genomic instability
Humans
Incidence
K‐ras mutation
Lung cancer
Lung Neoplasms - genetics
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
lung tumor
Lungs
Male
Medical research
Mice
Mice, Transgenic
Mutants
Mutation
p53 Protein
Protein Conformation
Proto-Oncogene Proteins p21(ras) - genetics
Sequence Analysis, DNA
TP53 mutant type
Transgenic animals
Transgenic mice
Transversion
Tumor Suppressor Protein p53 - chemistry
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Tumorigenesis
Tumors
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Summary: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. What's new? Mutations in TP53 and K‐ras frequently occur in non‐small cell lung cancer. Interactions between these two genes during lung tumorigenesis, however, are unknown. Here, contact‐(273H) and conformational‐(175H) mutations in TP53 were investigated for their role in lung tumorigenesis and for associations with K‐ras mutations. In TP53‐273H mice, transition mutations in K‐ras codon 61 dominated. Meanwhile, in TP53‐175H transgenic mice, transversion mutations in codons 12‐13 were the primary changes. K‐ras codon 12‐13 mutations occurred at a relatively early age in TP53‐175H mice, which also experienced accelerated lung cancer onset. The findings suggest that conformational TP53 mutations possess enhanced tumorigenic potential.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.32279