38. Comparative molecular genomic analyses of a Rhesus Lynch Syndrome model

      Colorectal cancer (CRC) is the third most common cancer in the U.S. Most CRC is sporadic, but Lynch Syndrome (LS) is the most common hereditary cancer syndrome predisposing to CRC and involves mismatch repair (MMR) deficiency. LS is secondary to germline mutations in one of four MMR genes (MLH1, MSH2, MSH6, and PMS2). Genetically engineered mouse models carrying germline mutations in MMR genes have significantly contributed to current understanding, but do not recapitulate the disease phenotype in LS patients and tissue-specific mouse models only do so partially. In contrast, the previously reported rhesus macaque (Macaca mulatta) model of Lynch Syndrome is potentially a more evolutionarily- and translationally-relevant animal model. Rhesus macaques within a closed breeding colony in Bastrop, TX carry exonic germline mutations in MLH1, which confers risk for spontaneously developing CRC with displaying clinico-pathologic symptoms similar to LS in humans. We performed genomic and transcriptomic characterization of these rhesus tumors using PCR-based determination of microsatellite instability (MSI), and total RNA sequencing. First, we designed a PCR-based MSI testing panel using six (6) modified MSI markers from commonly used human MSI markers to assess MSI in rhesus; second, we investigated the transcriptome of tumors including assessment of the CMS classification. Of 19 rhesus CRC cases, 10 were MSI-high, 6 were MSI-low, and 3 were MSI-stable. Transcriptomic analysis revealed differential gene expression profiles between MSI-high and MSI-stable levels in tumor tissues that recapitulate some of the main pathways observed in human specimens.
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