Abstract B29: A carcinogen-induced mouse model recapitulates the molecular alterations of human muscle-invasive bladder cancer

Abstract

Abstract Bladder cancer is the fourth most common cancer in men and fifth most common malignancy in the United States. Survival of patients with muscle-invasive or metastatic bladder cancer is poor, with only 35% survival at 5 years. Developing innovative anticancer drugs relies on the availability of model systems that closely recapitulate the corresponding human disease at both the histologic and molecular levels. One of the major limitations in the field of bladder cancer research is the limited availability of such models. The N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) mouse model is an attractive model system of muscle-invasive bladder cancer (MIBC) since it recapitulates the complex histology of human tumors in a background with intact immune system. However, it was unknown whether this carcinogen-induced model also mimicked human MIBC at the molecular and mutational level. In our study, we analyzed the mutational landscape of the BBN model by whole-exome sequencing followed by a bioinformatic comparison to human MIBC using genomic data from The Cancer Genome Atlas and other repositories. Similar to human MIBC, BBN tumors had a high mutation burden. Next, we extracted mouse-specific mutational signatures that correspond to different genetic instability processes operating in BBN tumors. Interestingly, one of these de novo extracted signatures aligned to a human mutational signature previously associated to DNA-repair deficiencies in human bladder cancers. We further analyzed the most commonly mutated genes and their intratumor mutation frequencies with the aim of identifying potential driver mutations. Our analyses converged on three genes that seem crucial in the process of tumorigenesis in both mouse and human bladder cancers: the tumor suppressor Trp53 as well as the genes Kmt2c and Kmt2d. These encode for methyltransferases involved in the methylation of histone H3K4 and play a key role in the epigenetic regulation of enhancer activity. Also, many of the putative driver mutations found in the BBN genomes corresponded to human cancer hotspot mutations, supporting their role as driver mutations. Together, our study revealed several similarities between human MIBC and the BBN mouse model. Our results highlighted the contribution of aberrations to chromatin regulators and genetic instability in both human and BBN bladder tumors, thus providing a strong rationale for the use of this mouse model in molecular and drug discovery studies. Citation Format: Damiano Fantini, Alexander P. Glaser, Rimar J. Kalen, Wang Yiduo, Yanni Yu, Joshua J. Meeks. A carcinogen-induced mouse model recapitulates the molecular alterations of human muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B29.