Msh2 and Apc mutated mouse models of colorectal cancer closely mimic the differences between Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis

Abstract

Introduction: Hereditary colorectal cancer occurs mainly in the setting of Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis. VCMsh2LoxP/LoxP and ApcMin/+ are mouse models of these two human syndromes. The goal of this study was to evaluate whether these two models recapitulate the differences observed between Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis. Matherials and Methods: Animals were characterized and compared regarding time to onset of disease and tumor incidence. Tumors were characterized regarding their histopathologic features, immune infiltrate through immunohistochemistry, and genetic alterations through whole-exome sequencing. Results: VCMsh2LoxP/LoxP mice show a longer average lifespan (367.9 days) comparatively to ApcMin/+ mice (135.4 days). ApcMin/+ mice showed a higher average incidence of intestinal tumors per animal (58.9) comparatively to VCMsh2LoxP/LoxP mice (3.54). The immune infiltrate was overall higher in VCMsh2LoxP/LoxP tumors with a significant difference for CD8+ T cells. The mean number of somatic genetic variants was significantly higher in tumors from VCMsh2LoxP/LoxP than from ApcMin/+ mice. Discussion: Compared to ApcMin/+, VCMsh2LoxP/LoxP mice have a significant increase in lifespan, significantly less tumors, an increased mutation burden and a greater lymphocyte infiltrate, with a significant difference in CD8+ T cells. These differences fully recapitulate the differences between Hereditary Nonpolyposis Colorectal Cancer and Familial Adenomatous Polyposis in humans. Conclusion: Results obtained with our preclinical mouse models are comparable and translatable to the respective human scenario, demonstrating they are appropriate models to study and compare intestinal tumorigenesis.