MSH2 and APC mutated mouse models 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. Materials and Methods: Animals were characterized and compared regarding time to disease manifestation and tumor incidence. Tumors were characterized regarding histopathologic features, immune infiltrate as evaluated by immunohistochemistry, and mutation burden through whole-exome sequencing. Results: VCMsh2LoxP/LoxP mice showed 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 in ApcMin/+ mice. Conclusions: Results obtained with these preclinical mouse models are comparable and translatable to the respective human scenario, demonstrating they are appropriate models to study and compare different models of intestinal tumorigenesis. These models are central to our understanding of colorectal tumorigenesis, including the role of microbiota in such processes.

Keywords

• gastrointestinal cancer
• cancer genetics
• hereditary intestinal cancer
• tumor infiltrating lymphocytes
• preclinical mouse models.