Figure 5 from Development and Application of MiMouse, a Comprehensive Genomic Profiling Panel for Credentialing Mouse Tumor Models

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posted on 2025-10-29, 07:40 authored by Kevin Hu, Chia-Jen Liu, Zhaoping Qin, Aaron M. Udager, Marcin P. Cieslik, Scott A. Tomlins

Genomic credentialing of increased FGA in fallopian tube HGSC and mouse genome arrangement–specific mechanisms of Smad4 loss in colorectal carcinoma by MiMouse. A, Comparison of gene-level FGA was performed between human (TCGA) HGSC and colorectal carcinoma (n = 572 and 592, respectively) and MiMouse-profiled GEMM HGSC and colorectal carcinoma tissues (n = 113 and 16, respectively) using the evaluable MiMouse autosomal gene set (n = 119); FGA from individual samples are plotted with box plots shown (P values from comparison of distributions by Wilcoxon rank-sum tests are shown). B,APC and SMAD4, two of the major tumor suppressors in colorectal carcinoma, show distinct genomic arrangement in humans vs. mice. Circos plot showing the syntenic mapping of APC/Apc and SMAD4/Smad4 in humans (peach) and mice (lavender). Syntenic linkages are colored by the different mappings of mouse chr 18, which harbors both genes in mice, to all syntenic human chromosomes; linkages to APC (human chr 5) and SMAD4 (human chr 18) are in black. C, Heatmap of aneuploidy by MiMouse for all evaluable colorectal carcinoma (10 adenomas and 28 carcinomas) samples is shown (red = gain; blue = loss). Individual mice, genotype, histology, and model type are indicated. Chromosomes found to be significantly gained are indicated in red; those significantly lost are in blue. The heatmap on right (chr11 and chr18) shows gene-level CN status (log2 CNR) according to the color scale, with the engineered Trp53 floxxed alleles (Trp53Del), the floxxed (Del) and unfloxxed Apc alleles, and Smad4 highlighted. Samples with Smad4 disruption through chr 18 aneuploidy (n = 5), focal Smad4 copy loss (n = 9), or prioritized Smad4 mutation (n = 1; black) are indicated. CRC, colorectal carcinoma.

Funding

A. Alfred Taubman Medical Research Institute (Taubman Institute)

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DOI - Is supplement to Development and Application of MiMouse, a Comprehensive Genomic Profiling Panel for Credentialing Mouse Tumor Models

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.