Figure 4 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

MiMouse for CGP and genomic credentialing across the neoplastic spectrum of two large cohorts of inducible fallopian tube (ovary) and colorectal (colorectal carcinoma) tumors. A, Promoters and transgenes used in the cohorts. Ovary and colorectal carcinoma tumor cohorts tested by MiMouse. Genes in bold were activated, and those in regular were inactivated; Trp53 (bold gray) was either inactivated through deletion or a point mutation was expressed (see main text for specific models). Abbreviations for genotypes (as used in the heatmap) are indicated. B, MiMouse cohort characteristics and CGP results from the ovary (predominantly HGSC; top, total n = 172) and colorectal carcinoma (bottom, total n = 100) cohorts are shown. Genotype, histology (CRC, carcinoma; eHGSC, early HGSC; HP, hyperplastic; Met., metastasis; MMMT, carcinosarcoma) and model type (GEMM, GEMM tumor tissue) are shown. Gene-level FGA (see main text) is shown according to the color scale (gray indicates no value due to QC failure, see Supplementary Fig. S9). All detected somatic, prioritized, amplifications (red), deep (homozygous) deletions (blue; none detected), and prioritized somatic mutations (black) across the cohorts are shown. C and D, CN plots of two colorectal carcinoma samples with focal amplifications in Myc or Pik3ca (indicated by arrows) are shown. The log2 CNR (vs. pseudo-normal) of individual amplicons are plotted, with genes (different colors) in genome order (chrs on bottom of plot) and gene-level log2 CNR indicated by black bars (black bars). E, CN plots of two histologically distinct HGSC tumors arising from both ovaries of the same mouse (1628LOT_X5 = left; MG1_X33 = right). Shared Myc amplifications are indicated. The remaining somatic CN profile (including gains in Arid1a and Csmd3 and loss of Mtor) is consistent with clonal origin [Trp53 (gray), which includes the engineered flox amplicons lost after induction and is shown for estimation of relative tumor content]. CRC, colorectal carcinoma.

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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.