High-throughput sequencing and in-silico analysis confirm pathogenicity of novel MSH3 variants in African American colorectal cancer.

Autor:	Rashid M; Department of Medicine, Gastroenterology Division, Department of Pathology and Cancer Center, Howard University College of Medicine, Washington, DC 20059, USA., Rashid R; Department of Medicine, Gastroenterology Division, Department of Pathology and Cancer Center, Howard University College of Medicine, Washington, DC 20059, USA., Gadewal N; Bioinformatics and Computational Biology Facility, Advanced Centre for Treatment, Research and Education in Cancer, Tata Memorial Centre, Kharghar, Navi Mumbai, MH 410210, India., Carethers JM; Division of Gastroenterology and Hepatology, Department of Medicine, UC San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA; Moores Cancer Center, and Herbert Wertheim School of Public Health and Human Longevity Science, UC San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA., Koi M; Division of Gastroenterology and Hepatology, Department of Medicine, UC San Diego, 9500 Gilman Dr, La Jolla, CA 92093, USA., Brim H; Department of Medicine, Gastroenterology Division, Department of Pathology and Cancer Center, Howard University College of Medicine, Washington, DC 20059, USA., Ashktorab H; Department of Medicine, Gastroenterology Division, Department of Pathology and Cancer Center, Howard University College of Medicine, Washington, DC 20059, USA. Electronic address: hashktorab@howard.edu.
Jazyk:	angličtina
Zdroj:	Neoplasia (New York, N.Y.) [Neoplasia] 2024 Mar; Vol. 49, pp. 100970. Date of Electronic Publication: 2024 Jan 27.
DOI:	10.1016/j.neo.2024.100970
Abstrakt:	The maintenance of DNA sequence integrity is critical to avoid accumulation of cancer-causing mutations. Inactivation of DNA Mismatch Repair (MMR) genes (e.g., MLH1 and MSH2) is common among many cancers, including colorectal cancer (CRC) and is the driver of classic microsatellite instability (MSI) in tumors. Somatic MSH3 alterations have been linked to a specific form of MSI called elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) that is associated with patient poor prognosis and elevated among African American (AA) rectal cancer patients. Genetic variants of MSH3 and their pathogenicity vary among different populations, such as among AA, which are not well-represented in publicly available databases. Targeted exome sequencing of MSH3 among AA CRC samples followed by computational bioinformatic pipeline and molecular dynamic simulation analysis approach confirmed six identified MSH3 variants (c.G1237A, c.C2759T, c.G1397A, c.G2926A, c.C3028T, c.G3241A) that corresponded to MSH3 amino-acid changes (p.E413K; p.S466N; p.S920F; p.E976K; p.H1010Y; p.E1081K). All identified MSH3 variants were non-synonymous, novel, pathogenic, and show loss or gain of hydrogen bonding, ionic bonding, hydrophobic bonding, and disulfide bonding and have a deleterious effect on the structure of MSH3 protein. Some variants were located within the ATPase site of MSH3, affecting ATP hydrolysis that is critical for MSH3's function. Other variants were in the MSH3-MSH2 interacting domain, important for MSH3's binding to MSH2. Overall, our data suggest that these variants among AA CRC patients affect the function of MSH3 making them pathogenic and likely contributing to the development or advancement of CRC among AA. Further clarifying functional studies will be necessary to fully understand the impact of these variants on MSH3 function and CRC development in AA patients. Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. (Copyright © 2024. Published by Elsevier Inc.)
Databáze:	MEDLINE
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