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

IF 3.3 Q3 ONCOLOGY
Kevin Hu, Chia-Jen Liu, Zhaoping Qin, Aaron M Udager, Marcin P Cieslik, Scott A Tomlins
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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. Here, we developed MiMouse, a mouse comprehensive genomic profiling panel for high throughput credentialling applicable to routine FFPE 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 (HGSC) GEMMs based on conditional inactivation of Brca1 (B), Trp53 (P), Pten (Pt), Rb1 (R), and/or Nf1 (N), and a colorectal carcinoma (CRC) GEMM based on conditional inactivation of Apc, Kras and/or P. We confirmed increased genomic instability in HGSC tumors, with BPPt cancers having both the shortest latency and the least genomic instability. In CRC, focusing on fidelity to human CRC 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 CRC models, has syntenic blocks from human chromosomes 7p, 7q and 13q, including Cdx2, which is both a lineage specific CRC oncogene and the CRC GEMM promoter source. Given the importance of mice to translational cancer research, this study highlights the considerations and utility of approaches for comprehensive genomic credentialling.

开发和应用MiMouse,一个全面的基因组分析面板,用于验证小鼠肿瘤模型。
尽管有共同的遗传驱动改变和组织学,但大多数小鼠肿瘤模型,包括那些基因工程(GEMM),与人类肿瘤模型的基因组保真度是未知的。在这里,我们开发了MiMouse,这是一种适用于常规FFPE肿瘤的高通量认证的小鼠全面基因组图谱面板。通过模拟/验证,我们重点考虑了跨物种突变优先排序,菌株确定和非整倍体检测。使用MiMouse,我们基于Brca1 (B)、Trp53 (P)、Pten (Pt)、Rb1 (R)和/或Nf1 (N)的条件失活,以及基于Apc、Kras和/或P的条件失活的结直肠癌(CRC) GEMM,分析了来自高级别浆液性癌(HGSC) GEMM的bbbb250个肿瘤。我们证实HGSC肿瘤的基因组不稳定性增加,BPPt癌症具有最短的潜伏期和最小的基因组不稳定性。在CRC研究中,关注人类CRC非整倍性事件的保真度,我们的研究结果强调了转基因研究中同质性的关键重要性,因为不仅小鼠18号染色体(含有肿瘤抑制基因Smad4)的缺失是一个显著的非整倍性事件(18%),其他肿瘤也存在局灶性Smad4拷贝丢失,可能是由于小鼠特异性的Apc邻近(小鼠和人类分别为18号和5号染色体)。同样,小鼠5号染色体是我们CRC模型中唯一显著获得的(46%)染色体,它具有来自人类染色体7p、7q和13q的合成块,包括Cdx2,它既是一个谱系特异性CRC癌基因,也是CRC GEMM启动子的来源。鉴于小鼠对转化性癌症研究的重要性,本研究强调了综合基因组认证方法的考虑和效用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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