The most common mutation in human colon cancer is inactivation of adenomatous polyposis coli (APC), a key inhibitor of the Wnt/β-catenin pathway. If left untreated, all humans carrying germline APC-inactivating mutations will develop colon cancer by the age of forty. In addition, truncation of APC is the primary contributor to sporadic colon cancer in humans. In zebrafish, the same truncated mutation in apc also causes digestive tract neoplasia. However, the incidence of tumors outside the intestinal system in the apc mutant zebrafish has not been reported. To determine if other tumors arise at high frequencies in the apc mutant, we monitored several cohorts of zebrafish derived from apc(hu147/+) incrosses on a weekly basis over a one-year period, covering the age of 6 to 18 months post-fertilization. Specimens displaying evidence of tumors or general signs of declining health were euthanized, photographed, tail-clipped for genotypic analysis, and then fixed and embedded in paraffin for histological examination. Analysis of the data showed that 1.2% of the apc(hu147/+) zebrafish had abnormally distended abdomens (possibly from intestinal neoplasia), and 1.8% of the mutants developed olfactory neuroblastoma (esthesioneuroblastoma). We have yet to detect a single wild-type fish with esthesioneuroblastoma in these cohorts. Overall, the results indicate that our apc(hu147/+) zebrafish exhibit a remarkably increased incidence of esthesioneuroblastoma compared to wild-type fish or other tumor-prone mutants. Furthermore, relative to the latter, our apc(hu147/+) zebrafish begin developing tumors of any type at an earlier age. Histopathological examination showed these esthesioneuroblastoma tumors to be highly invasive. No previous reports indicate that ethesioneuroblastoma is a common tumor type in apc(hu147/+) zebrafish. Therefore, we propose to have discovered a new modifier mutation, which leads to hyperproliferation of olfactory neuroepithelium in response to dysregulation of the Wnt/β-catenin pathway. Identification of this mutant gene is expected to shed light on interactions of tissue-specific regulators with components of the Wnt/β-catenin signaling pathway to control rates of cell proliferation and differentiation.

Citation Format: Vivianne E. Greenwood, Noah Museles, Quinn Weinberg, Eric Glasgow. High rates of esthesioneuroblastoma in adenomatous polyposis coli (apc) mutant zebrafish suggest a new modifier mutation altering tissue specificity of Wnt/β-catenin-dependent hyperproliferation. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4296. doi:10.1158/1538-7445.AM2013-4296