Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer.
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 repa...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-04-01
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| Series: | PLoS Genetics |
| Online Access: | https://doi.org/10.1371/journal.pgen.1010163 |
| _version_ | 1797837894498385920 |
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| author | Nejla Ozirmak Lermi Stanton B Gray Charles M Bowen Laura Reyes-Uribe Beth K Dray Nan Deng R Alan Harris Muthuswamy Raveendran Fernando Benavides Carolyn L Hodo Melissa W Taggart Karen Colbert Maresso Krishna M Sinha Jeffrey Rogers Eduardo Vilar |
| author_facet | Nejla Ozirmak Lermi Stanton B Gray Charles M Bowen Laura Reyes-Uribe Beth K Dray Nan Deng R Alan Harris Muthuswamy Raveendran Fernando Benavides Carolyn L Hodo Melissa W Taggart Karen Colbert Maresso Krishna M Sinha Jeffrey Rogers Eduardo Vilar |
| author_sort | Nejla Ozirmak Lermi |
| collection | DOAJ |
| description | 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), transcriptomics 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-H) 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. |
| first_indexed | 2024-04-09T15:33:06Z |
| format | Article |
| id | doaj.art-3345afdd7e5447958a5094fe6c001467 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-09T15:33:06Z |
| publishDate | 2022-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj.art-3345afdd7e5447958a5094fe6c0014672023-04-28T05:31:17ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042022-04-01184e101016310.1371/journal.pgen.1010163Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer.Nejla Ozirmak LermiStanton B GrayCharles M BowenLaura Reyes-UribeBeth K DrayNan DengR Alan HarrisMuthuswamy RaveendranFernando BenavidesCarolyn L HodoMelissa W TaggartKaren Colbert MaressoKrishna M SinhaJeffrey RogersEduardo VilarColorectal 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), transcriptomics 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-H) 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.https://doi.org/10.1371/journal.pgen.1010163 |
| spellingShingle | Nejla Ozirmak Lermi Stanton B Gray Charles M Bowen Laura Reyes-Uribe Beth K Dray Nan Deng R Alan Harris Muthuswamy Raveendran Fernando Benavides Carolyn L Hodo Melissa W Taggart Karen Colbert Maresso Krishna M Sinha Jeffrey Rogers Eduardo Vilar Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer. PLoS Genetics |
| title | Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer. |
| title_full | Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer. |
| title_fullStr | Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer. |
| title_full_unstemmed | Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer. |
| title_short | Comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer. |
| title_sort | comparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair deficient colorectal cancer |
| url | https://doi.org/10.1371/journal.pgen.1010163 |
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