Abstract
BackgroundMutations in the P53 gene are among the most common genetic abnormalities in human lung cancer. Codon 273 in the sequence-specific DNA binding domain is one of the most frequently mutated sites.MethodologyTo investigate the role of mutant p53 in lung tumorigenesis, a lung specific p53(273H) transgenic mouse model was developed. Rates of lung cancer formation in the transgenic animals and their littermates were evaluated by necropsy studies performed in progressive age cohorts ranging from 4 to 24 months. In order to establish the influence of other common genetic abnormalities in lung tumor formation in the animals, K-Ras gene mutation and p16INK4a (p16) promoter methylation were evaluated in a total of 281 transgenic mice and 189 non-transgenic littermates.Principal FindingsAt the age extremes of 4–12 and 22–24 months no differences were observed, with very low prevalence of tumors in animals younger than 12 months, and a relatively high prevalence at age 22 months or older. However, the transgenic mice had a significant higher lung tumor rate than their non-transgenic counterparts during the age of 13–21 months, suggesting an age-related shift in lung tumor formation induced by the lung-specific expression of the human mutant p53. Histopathology suggested a more aggressive nature for the transgenic tumors. Older mice (>13 months) had a significantly higher rate of p16 promoter methylation (17% v 82%). In addition, an age related effect was observed for K-Ras codons 12 or 13 mutations, but not for codon 61 mutations.Conclusions/SignificanceThese results would suggest that the mutant p53(273H) contributes to an acceleration in the development of spontaneous lung tumors in these mice. Combination with other genetic and epigenetic alterations occurring after the age of 13 months is intimately linked to its oncogenic potential.
Highlights
Lung cancer is one of the most deadly cancers worldwide [1,2,3], and with more than 160,000 deaths per year
Seventy-five to eighty-five percent of lung cancers are categorized as non-small cell cancers (NSCLC); and adenocarcinoma has become the most prevalent NSCLC subtype [1,3]
We have developed a line of transgenic mice expressing the human p53(273H) gene under the transcriptional control of the human surfactant protein C (SP-C) promoter [23]
Summary
Lung cancer is one of the most deadly cancers worldwide [1,2,3], and with more than 160,000 deaths per year. It has been reported that 50–60% of non-small cell lung cancers and 90% of small cell lung tumors contain p53 mutations; p53 alterations are among the most common genetic events in this malignancy [4,5]. The majority of p53 mutations are missense and found within the sequence-specific DNA-binding domain. Unlike most tumor-derived mutant p53 proteins, p53(273H) retains partial sequence-specific DNA-binding and transcriptional activation functions [14,15,16,17]. Mutations in the P53 gene are among the most common genetic abnormalities in human lung cancer. Codon 273 in the sequence-specific DNA binding domain is one of the most frequently mutated sites
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