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- Title
Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer.
- Authors
Ozirmak Lermi, Nejla; Gray, Stanton B.; Bowen, Charles M.; Reyes-Uribe, Laura; Dray, Beth K.; Deng, Nan; Harris, R. Alan; Raveendran, Muthuswamy; Benavides, Fernando; Hodo, Carolyn L.; Taggart, Melissa W.; Colbert Maresso, Karen; Sinha, Krishna M.; Rogers, Jeffrey; Vilar, Eduardo
- Abstract
Colorectal cancer (CRC) remains the third most common cancer in the US with 15% of cases displaying Microsatellite Instability (MSI) secondary to Lynch Syndrome (LS) or somatic hypermethylation of the MLH1 promoter. A cohort of rhesus macaques from our institution developed spontaneous mismatch repair deficient (MMRd) CRC with a notable fraction harboring a pathogenic germline mutation in MLH1 (c.1029C<G, p.Tyr343Ter). Our study aimed to provide a detailed molecular characterization of rhesus CRC for cross-comparison with human MMRd CRC. We performed PCR-based MSI testing (n = 41), transcriptomic analysis (n = 35), reduced-representation bisulfite sequencing (RRBS) (n = 28), and MLH1 DNA methylation (n = 10) using next-generation sequencing (NGS) of rhesus CRC. Systems biology tools were used to perform gene set enrichment analysis (GSEA) for pathway discovery, consensus molecular subtyping (CMS), and somatic mutation profiling. Overall, the majority of rhesus tumors displayed high levels of MSI (MSI-high) and differential gene expression profiles that were consistent with known deregulated pathways in human CRC. DNA methylation analysis exposed differentially methylated patterns among MSI-H, MSI-L (MSI-low)/MSS (MS-stable) and LS tumors with MLH1 predominantly inactivated among sporadic MSI-H CRCs. The findings from this study support the use of rhesus macaques as an alternative animal model to mice to study carcinogenesis, develop immunotherapies and vaccines, and implement chemoprevention approaches relevant to sporadic MSI-H and LS CRC in humans. Author summary: CRC remains the third most common cancer diagnosed in the United States. Some CRC may arise spontaneously without any known risk factors, while others may arise in patients with strong family history associated to inherited genetic syndromes. Our study focused on a genetic condition known as LS, which significantly increases the risk of developing CRC as well as several different types of cancers. Biological tools and laboratory animal models available for studying hereditary CRC remain limited and not always directly translatable to human disease. Therefore, our study presents a comprehensive analysis of a spontaneous non-human primate (NHP) model used to study the genetic contribution in Lynch Syndrome colorectal cancer. We performed a cross-comparison of different types of CRC in humans with tumors developed in monkeys to determine the accuracy of using this NHP model for studying early cancer development, treatment options, and prevention approaches in both hereditary and sporadic colorectal cancer displaying MMR deficiency.
- Subjects
UNITED States; MACAQUES; RHESUS monkeys; COLORECTAL cancer; GENOMICS; HEREDITARY nonpolyposis colorectal cancer; GENE expression profiling
- Publication
PLoS Genetics, 2022, Vol 18, Issue 4, p1
- ISSN
1553-7390
- Publication type
Article
- DOI
10.1371/journal.pgen.1010163