{"title":"高通量测序和实验室分析证实了新型 MSH3 变异在非裔美国人结直肠癌中的致病性。","authors":"Mudasir Rashid , Rumaisa Rashid , Nikhil Gadewal , John M. Carethers , Minoru Koi , Hassan Brim , Hassan Ashktorab","doi":"10.1016/j.neo.2024.100970","DOIUrl":null,"url":null,"abstract":"<div><p>The maintenance of DNA sequence integrity is critical to avoid accumulation of cancer-causing mutations. Inactivation of DNA Mismatch Repair (MMR) genes (e.g., <em>MLH1</em> and <em>MSH2</em>) is common among many cancers, including colorectal cancer (CRC) and is the driver of classic microsatellite instability (MSI) in tumors. Somatic <em>MSH3</em> 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 <em>MSH3</em> and their pathogenicity vary among different populations, such as among AA, which are not well-represented in publicly available databases. Targeted exome sequencing of <em>MSH3</em> among AA CRC samples followed by computational bioinformatic pipeline and molecular dynamic simulation analysis approach confirmed six identified <em>MSH3</em> variants (c.G1237A, c.C2759T, c.G1397A, c.G2926A, c.C3028T, c.G3241A) that corresponded to MSH3 amino-acid changes (<em>p.</em>E413K; <em>p.</em>S466N; <em>p.</em>S920F; <em>p.</em>E976K; <em>p.</em>H1010Y; <em>p.</em>E1081K). All identified <em>MSH3</em> 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.</p></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":null,"pages":null},"PeriodicalIF":4.8000,"publicationDate":"2024-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1476558624000071/pdfft?md5=cab8958f4c72a1490aa1f60da31e9c51&pid=1-s2.0-S1476558624000071-main.pdf","citationCount":"0","resultStr":"{\"title\":\"High-throughput sequencing and in-silico analysis confirm pathogenicity of novel MSH3 variants in African American colorectal cancer\",\"authors\":\"Mudasir Rashid , Rumaisa Rashid , Nikhil Gadewal , John M. Carethers , Minoru Koi , Hassan Brim , Hassan Ashktorab\",\"doi\":\"10.1016/j.neo.2024.100970\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The maintenance of DNA sequence integrity is critical to avoid accumulation of cancer-causing mutations. Inactivation of DNA Mismatch Repair (MMR) genes (e.g., <em>MLH1</em> and <em>MSH2</em>) is common among many cancers, including colorectal cancer (CRC) and is the driver of classic microsatellite instability (MSI) in tumors. Somatic <em>MSH3</em> 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 <em>MSH3</em> and their pathogenicity vary among different populations, such as among AA, which are not well-represented in publicly available databases. Targeted exome sequencing of <em>MSH3</em> among AA CRC samples followed by computational bioinformatic pipeline and molecular dynamic simulation analysis approach confirmed six identified <em>MSH3</em> variants (c.G1237A, c.C2759T, c.G1397A, c.G2926A, c.C3028T, c.G3241A) that corresponded to MSH3 amino-acid changes (<em>p.</em>E413K; <em>p.</em>S466N; <em>p.</em>S920F; <em>p.</em>E976K; <em>p.</em>H1010Y; <em>p.</em>E1081K). All identified <em>MSH3</em> 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.</p></div>\",\"PeriodicalId\":18917,\"journal\":{\"name\":\"Neoplasia\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2024-01-27\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S1476558624000071/pdfft?md5=cab8958f4c72a1490aa1f60da31e9c51&pid=1-s2.0-S1476558624000071-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Neoplasia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1476558624000071\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"Biochemistry, Genetics and Molecular Biology\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neoplasia","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1476558624000071","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"Biochemistry, Genetics and Molecular Biology","Score":null,"Total":0}
High-throughput sequencing and in-silico analysis confirm pathogenicity of novel MSH3 variants in African American colorectal cancer
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.
期刊介绍:
Neoplasia publishes the results of novel investigations in all areas of oncology research. The title Neoplasia was chosen to convey the journal’s breadth, which encompasses the traditional disciplines of cancer research as well as emerging fields and interdisciplinary investigations. Neoplasia is interested in studies describing new molecular and genetic findings relating to the neoplastic phenotype and in laboratory and clinical studies demonstrating creative applications of advances in the basic sciences to risk assessment, prognostic indications, detection, diagnosis, and treatment. In addition to regular Research Reports, Neoplasia also publishes Reviews and Meeting Reports. Neoplasia is committed to ensuring a thorough, fair, and rapid review and publication schedule to further its mission of serving both the scientific and clinical communities by disseminating important data and ideas in cancer research.