Development and Application of MiMouse, a Comprehensive Genomic Profiling Panel for Credentialing Mouse Tumor Models

Despite shared genetic driver alterations and histology, the genomic fidelity of most mouse tumor models, including those genetically engineered (GEMM), to their human counterparts is unknown. In this study, we developed MiMouse, a mouse comprehensive genomic profiling panel for high-throughput credentialing applicable to routine formalin-fixed, paraffin-embedded tumors. Through simulation/validation, we focused on considerations for cross-species mutation prioritization, strain determination, and aneuploidy detection. Using MiMouse, we profiled >250 tumors from high-grade serous carcinoma GEMMs based on conditional inactivation of Brca1 (B), Trp53 (P), Pten (Pt), Rb1 (R), and/or Nf1 (N) and a colorectal carcinoma GEMM based on conditional inactivation of Apc, Kras, and/or P. We confirmed increased genomic instability in high-grade serous carcinoma tumors, with BPPt cancers having both the shortest latency and the least genomic instability. In colorectal cancer, focusing on fidelity to human colorectal cancer aneuploidy events, our results highlighted the critical importance of synteny in transgenic studies, as not only was loss of mouse chromosome 18 (containing the tumor suppressor gene Smad4) a significant aneuploidy event (18%), additional tumors harbored focal Smad4 copy loss, potentially due to the mouse-specific proximity of Apc (mouse and human chromosomes 18 and 5, respectively). Likewise, mouse chromosome 5, the only significantly gained (46%) chromosome in our colorectal cancer models, has syntenic blocks from human chromosomes 7p, 7q, and 13q, including Cdx2, which is both a lineage-specific colorectal cancer oncogene and the colorectal cancer GEMM promoter source. Given the importance of mice to translational cancer research, this study highlights the considerations and utility of approaches for comprehensive genomic credentialing.

The genomic fidelity of most mouse tumor models is unknown. Considering cross-species issues, we develop MiMouse for high-throughput genomic credentialing and profile >250 tumors from fallopian tube and colorectal tumor models.