<p>Overview of the development and application of MiMouse for mouse CGP and genomic credentialing. Human (peach)- and mouse (lavender)-specific resources were considered through simulations to develop MiMouse, a 135-gene (0.5 Mb) CGP assay designed to be compatible with minute GEMM tumor lesions from all stages of neoplasia. Validation for various alteration and genomic signature classes was performed using a combination of orthogonal technologies. We applied MiMouse to a large cohort of tumors from fallopian tube (ovary) and colorectal (colorectal carcinoma) models; see <a href="#fig4" target="_blank">Fig. 4</a> for detailed genotypes and histology. In addition to standard CGP profiling and demonstration of utility for genomic credentialing (e.g., comparison of FGA between human and mouse ovary vs. colorectal carcinoma tumors), our study of aneuploidy in colorectal carcinoma tumors highlighted the importance of synteny. For example, two key tumor suppressors, <i>APC</i>/<i>Apc</i> and <i>SMAD4</i>/<i>Smad4</i>, show unique arrangement in humans (on separate chrs) and mice (both on chr 18). Likewise, in humans, three peaks (spanning from 13q12.2-33.3) have been identified in the recurrent, highly colorectal carcinoma–specific 13q gain; this region maps to five distinct mouse chrs. Images of human-specific resources were from cBioPortal (<a href="#bib57" target="_blank">57</a>); the synteny resource image was from Jax synteny browser (<a href="#bib126" target="_blank">126</a>). CRC, colorectal carcinoma.</p>
ARTICLE ABSTRACT
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.
