Open AccessComparative molecular genomic analyses of a spontaneous rhesus macaque model of mismatch repair-deficient colorectal cancer
Author(s) -
Nejla Ozirmak Lermi,
Stanton B. Gray,
Charles M. Bowen,
Laura Reyes-Uribe,
Beth 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
Publication year - 2022
Publication title -
plos genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.587
H-Index - 233
eISSN - 1553-7404
pISSN - 1553-7390
DOI - 10.1371/journal.pgen.1010163
Subject(s) - mlh1 , biology , microsatellite instability , lynch syndrome , dna mismatch repair , dna methylation , colorectal cancer , germline mutation , cancer research , genetics , rhesus macaque , carcinogenesis , cancer , gene , mutation , microsatellite , gene expression , allele
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.