Abstract 1906: MSH3: An underestimated DNA MMR gene in colorectal carcinogenesis and its potential role in disparity

Abstract

Abstract Background: Unique mutations in cancer genes have been found in different races including African Americans (AA) population. Maintenance of proficient mismatch repair genes is important in colorectal cancer. Among them, MSH3 is found to be more important in colorectal cancer in AA particularly as its alterations associate with EMAST phenotype that has poor prognosis. However, there are regional variations in the classification and criteria used to determine the pathogenicity of these mutations particularly in AA due to their high genomic diversity. Aim: To analyze unique and novel MSH3 mutations using specific in-silico prediction tools and to validate their biological significances in AA-CRC. Results: In this study, we validated our targeted exome sequencing data of MSH3 mutations in AA and Caucasians (CA) CRC samples. A cost effective in-silico approach was employed to narrow down most significant MSH3 mutations. Interestingly, we and found six non-synonymous novel, pathogenic mutations in MSH3 gene (c.G1237A, c.C2759T, c.G1397A, c.G2926A, c.C3028T, c.G3241A) correspond to MSH3 protein (E413K; S466N; S920F; E976K; H1010Y; E1081K), in AA than CA samples. Also, we observed loss or gain of different chemical bonding patterns (hydrogen, ionic, hydrophobic, and di-sulfide bonding) between wild type and mutant MSH3 protein. Interestingly, some of these mutations were within the ATPase site while others are in MSH3-MSH2 interacting domains. Furthermore, Molecular Dynamics Simulation (MDS) of these six mutants of MSH3 proteins showed an overall effect on MSH3 protein stability especially in MSH3-MSH2 interaction compared to wild type MSH3 protein.Conclusion: Our data showed that, six MSH3 non-synonymous mutations are deleterious as they affect important sites within MSH3-MSH2 interactive and ATPase domain. Assessing the real frequency of these mutations in large cohort and their specific effect on function may shed light on EMAST phenotype, high prevalence, and overall poor prognosis in the AA population. In vitro functional assays using CRISPR-Cas9 knock-in and in vivo studies are underway to mimic these mutations. Citation Format: Mudasir Rashid, Rumaisa Rashid, Minoru Koi, John M. Carethers, Hassan Brim, Hassan Ashktorab. MSH3: An underestimated DNA MMR gene in colorectal carcinogenesis and its potential role in disparity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1906.