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。

IF 4.8 2区 医学 Q1 Biochemistry, Genetics and Molecular Biology Neoplasia Pub Date : 2024-01-27 DOI:10.1016/j.neo.2024.100970
Mudasir Rashid , Rumaisa Rashid , Nikhil Gadewal , John M. Carethers , Minoru Koi , Hassan Brim , Hassan Ashktorab
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引用次数: 0

摘要

保持 DNA 序列的完整性对于避免致癌突变的积累至关重要。DNA错配修复(MMR)基因(如MLH1和MSH2)失活在包括结直肠癌(CRC)在内的许多癌症中很常见,是肿瘤中典型的微卫星不稳定性(MSI)的驱动因素。体细胞 MSH3 基因变异与一种特殊形式的 MSI 有关,这种 MSI 被称为 "选定四核苷酸重复序列微卫星变异升高"(EMAST),它与患者的不良预后有关,并且在非裔美国人(AA)直肠癌患者中升高。MSH3的基因变异及其致病性在不同人群(如非裔美国人)中各不相同,而非裔美国人在公开数据库中的代表性并不高。通过计算生物信息学管道和分子动态模拟分析方法对AA CRC样本中的MSH3进行靶向外显子测序,证实了6个已发现的MSH3变体(c.G1237A、c.C2759T、c.G1397A、c.G2926A、c.C3028T、c.G3241A),这些变异与MSH3氨基酸变化(p.E413K;p.S466N;p.S920F;p.E976K;p.H1010Y;p.E1081K)相对应。所有已发现的 MSH3 变异均为非同义、新颖、致病性变异,表现为氢键、离子键、疏水键和二硫键的缺失或增益,并对 MSH3 蛋白的结构产生有害影响。一些变异位于 MSH3 的 ATPase 位点,影响了对 MSH3 功能至关重要的 ATP 水解。其他变异位于 MSH3-MSH2 相互作用结构域,对 MSH3 与 MSH2 的结合非常重要。总之,我们的数据表明,AA 族 CRC 患者中的这些变异影响了 MSH3 的功能,使其成为致病基因,并可能导致 AA 族 CRC 的发展或恶化。要全面了解这些变异对 AA 患者 MSH3 功能和 CRC 发展的影响,有必要进一步开展明确的功能研究。
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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.

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来源期刊
Neoplasia
Neoplasia 医学-肿瘤学
CiteScore
9.20
自引率
2.10%
发文量
82
审稿时长
26 days
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.
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