Carcinogen‐induced tumors in SFN‐transgenic mice harbor a characteristic mutation spectrum of human lung adenocarcinoma

Abstract

The landscape of genetic alterations in disease models such as transgenic mice or mice with carcinogen‐induced tumors has provided a huge amount of information that has shed light on the process of tumorigenesis in human non‐small‐cell lung cancer (NSCLC). We have previously identified stratifin (SFN) as a potent oncogene, and generated SFN‐transgenic (Tg‐SPC‐SFN+/−) mice, which express human SFN (hSFN) only in the lung. Here, we have found that carcinogen nicotine‐derived nitrosaminoketone (NNK)‐induced tumors developing in Tg‐SPC‐SFN+/− mice show a similar histology to human lung adenocarcinoma and exhibit high hSFN expression. In order to compare the genetic characteristics of Tg‐SPC‐SFN+/− tumors and human lung adenocarcinoma, the former were subjected to whole‐exome sequencing. Interestingly, Tg‐SPC‐SFN+/− tumors showed the distinct distribution of exonic mutations and high number of mutated genes and transversion. Moreover, Tg‐SPC‐SFN+/− tumors showed 73 genes that were commonly detected in more than 2 tumors, mutations of which were also found in human lung adenocarcinoma. The expression levels of some of these genes were significantly associated with the clinical outcome of lung adenocarcinoma patients. Additionally, mutated genes in Tg‐SPC‐SFN+/− tumors were closely associated with key canonical pathways such as PI3K/AKT signaling and apoptosis signaling. These results suggest that SFN overexpression is a universal abnormality in human lung adenocarcinogenesis and Tg‐SPC‐SFN+/− tumors recapitulate key features of major human lung adenocarcinoma. Therefore, Tg‐SPC‐SFN+/− mice provide a useful model for clarifying the molecular mechanism underlying lung adenocarcinogenesis.

Significance of stratifin in early progression of lung adenocarcinoma and its potential therapeutic relevance

“…In addition, Tg-SPC-SFN +/− tumors were subjected to whole-exome sequencing to investigate their genetic characteristics. Of note, Tg-SPC-SFN +/− tumors showed a distinct signature that is similar to the COSMIC signatures 4 and 24, 33 which show a high frequency of C > A. 57 Consistent with our results, TCGA also indicated that signatures 4 and 24 were frequently observed in human lung adenocarcinoma and showed a high frequency of C > A and C > T substitutions.…”

“…58 As the mean Ts/Tv ratio for Tg-SPC-SFN +/− tumors was 0.34, being similar to that for human lung adenocarcinoma (Ts/Tv = 0.44), Tg-SPC-SFN +/− tumors might have characteristics comparable to those of human lung adenocarcinoma. 33 Tg-SPC-SFN +/− tumors showed 73 genes that were commonly detected in multiple tumor samples, mutations of which were also found in human lung adenocarcinoma. The expression levels of some of these genes were significantly associated with the clinical outcome of lung adenocarcinoma patients.…”

“…The induction of SFN is mediated by a p53-responsive element located 1.8 kb upstream of its transcription start site. 42 SFN sequesters the mitotic initiation complex, cdc2-cyclin B1, and prevents it from entering the nucleus, 29,32,33 thus preventing initiation of mitosis. 43 Phan et al have also reported that SFN negatively regulates the tumor-promoting metabolic program by enhancing c-Myc ubiquitination and degradation.…”

“…These results suggest that SFN overexpression is a universal abnormality in human lung adenocarcinogenesis and that Tg-SPC-SFN +/− tumors recapitulate the key features of major human lung adenocarcinoma. 33 Therefore, Tg-SPC-SFN +/− mice provide a useful model for clarifying the molecular mechanisms underlying lung adenocarcinogenesis.…”