Tumor-specific microsatellite instability: do distinct mechanisms underlie the MSI-L and EMAST phenotypes?
Tumor-specific microsatellite instability: do distinct mechanisms underlie the MSI-L and EMAST phenotypes?
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DOI：
10.1016/j.mrfmmm.2012.11.003
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发表时间：
2013-03
影响因子：
2.3
通讯作者：
Eckert, Kristin A.
中科院分区：
文献类型：
--
作者：
Hile, Suzanne E.;Shabashev, Samion;Eckert, Kristin A.
关键词：
微卫星 DNA 序列显示肿瘤组织中的等位基因长度改变或微卫星不稳定性 (MSI)，MSI 在诊断上用于肿瘤检测和分类。我们讨论已知的肿瘤特异性 MSI 模式类型以及每种模式背后的相关机制。各个微卫星的突变率差异很大，基序大小、序列和长度等内在 DNA 特征导致了这种差异。 MSI 用于检测错配修复 (MMR) 缺陷的肿瘤，这些肿瘤由于全基因组微卫星不稳定而表现出 MSI 高表型。由于多种途径维持微卫星稳定性，因此经历了与中度基因组不稳定性相关的其他事件的肿瘤可能仅在特定的单、二或四核苷酸标记物上显示诊断性 MSI。我们总结了散发性癌症中此类替代 MSI 形式 (A-MSI) 的证据，也称为 MSI-Low 和 EMAST。虽然 A-MSI 的存在没有争议，但对该现象的起源和病理意义存在分歧。尽管 PCR 方法引起的模糊性可能是一个来源，但存在其他机制的证据可以解释肿瘤特异性 A-MSI。 A-MSI 肿瘤的某些部分可能是由肿瘤细胞进化过程中出现的随机突变事件引起的。然而，这种机制无法解释 A-MSI 对二核苷酸和四核苷酸不稳定性的特异性。我们提出了支持另一种论点的证据，即一些 A-MSI 肿瘤是由独特的遗传途径产生的，并给出了 DNA 代谢途径的例子，这些途径在改变时可能导致特定微卫星基序的不稳定。最后，我们认为肿瘤中的 A-MSI 可能是环境影响和 DNA 损伤的分子特征。重要的是，A-MSI 发生在多种肿瘤前炎症状态中，包括炎症性肠病，这与氧化应激在 A-MSI 中的作用一致。了解 A-MSI 肿瘤表型的生化基础将促进新诊断工具的开发，并对个体癌症的临床管理产生积极影响。
Microsatellite DNA sequences display allele length alterations or microsatellite instability (MSI) in tumor tissues, and MSI is used diagnostically for tumor detection and classification. We discuss the known types of tumor-specific MSI patterns and the relevant mechanisms underlying each pattern. Mutation rates of individual microsatellites vary greatly, and the intrinsic DNA features of motif size, sequence, and length contribute to this variation. MSI is used for detecting mismatch repair (MMR)-deficient tumors, which display an MSI-High phenotype due to genome-wide microsatellite destabilization. Because several pathways maintain microsatellite stability, tumors that have undergone other events associated with moderate genome instability may display diagnostic MSI only at specific mono-, di- or tetranucleotide markers. We summarize evidence for such alternative MSI forms (A-MSI) in sporadic cancers, also referred to as MSI-Low and EMAST. While the existence of A-MSI is not disputed, there is disagreement about the origin and pathologic significance of this phenomenon. Although ambiguities due to PCR methods may be a source, evidence exists for other mechanisms to explain tumor-specific A-MSI. Some portion of A-MSI tumors may result from random mutational events arising during neoplastic cell evolution. However, this mechanism fails to explain the specificity of A-MSI for di- and tetranucleotide instability. We present evidence supporting the alternative argument that some A-MSI tumors arise by a distinct genetic pathway, and give examples of DNA metabolic pathways that, when altered, may be responsible for instability at specific microsatellite motifs. Finally, we suggest that A-MSI in tumors could be molecular signatures of environmental influences and DNA damage. Importantly, A-MSI occurs in several preneoplastic inflammatory states, including inflammatory bowel diseases, consistent with a role of oxidative stress in A-MSI. Understanding the biochemical basis of A-MSI tumor phenotypes will advance the development of new diagnostic tools and positively impact the clinical management of individual cancers.
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人胃癌相关的DNA聚合酶β变异D160N是一种诱导细胞转化的突变器。
影响因子：
3.8
作者：
Donigan, Katherine A.;Hile, Suzanne E.;Eckert, Kristin A.;Sweasy, Joann B.
通讯作者：
Sweasy, Joann B.
影响因子：
2.9
作者：
Dalal, S;Hile, S;Sweasy, JB
通讯作者：
Sweasy, JB
影响因子：
8
作者：
Catto, JWF;Azzouzi, AR;Meuth, M
通讯作者：
Meuth, M
影响因子：
4.8
作者：
Donigan, Katherine A.;Sun, Ka-Wai;Sweasy, Joann B.
通讯作者：
Sweasy, Joann B.
DOI：
10.1007/s11605-010-1340-6
发表时间：
2010-10
期刊：
Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract
影响因子：
--
作者：
Devaraj B;Lee A;Cabrera BL;Miyai K;Luo L;Ramamoorthy S;Keku T;Sandler RS;McGuire KL;Carethers JM
通讯作者：
Carethers JM