Clonal expansion of cancer driver gene mutants investigated using advanced sequencing technologies

IF 6.4 2区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Mutation Research-Reviews in Mutation Research Pub Date : 2024-07-01 DOI:10.1016/j.mrrev.2024.108514
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Abstract

Advanced sequencing technologies (ASTs) have revolutionized the quantitation of cancer driver mutations (CDMs) as rare events, which has utility in clinical oncology, cancer research, and cancer risk assessment. This review focuses on studies that have used ASTs to characterize clonal expansion (CE) of cells carrying CDMs and to explicate the selective pressures that shape CE. Importantly, high-sensitivity ASTs have made possible the characterization of mutant clones and CE in histologically normal tissue samples, providing the means to investigate nascent tumor development. Some ASTs can identify mutant clones in a spatially defined context; others enable integration of mutant data with analyses of gene expression, thereby elaborating immune, inflammatory, metabolic, and/or stromal microenvironmental impacts on CE. As a whole, these studies make it clear that a startlingly large fraction of cells in histologically normal tissues carry CDMs, CDMs may confer a context-specific selective advantage leading to CE, and only a small fraction of cells carrying CDMs eventually result in neoplasia. These observations were integrated with available literature regarding the mechanisms underlying clonal selection to interpret how measurements of CDMs and CE can be interpreted as biomarkers of cancer risk. Given the stochastic nature of carcinogenesis, the potential functional latency of driver mutations, the complexity of potential mutational and microenvironmental interactions, and involvement of other types of genetic and epigenetic changes, it is concluded that CDM-based measurements should be viewed as probabilistic rather than deterministic biomarkers. Increasing inter-sample variability in CDM levels (as a consequence of CE) may be interpretable as a shift away from normal tissue homeostasis and an indication of increased future cancer risk, a process that may reflect normal aging or carcinogen exposure. Consequently, analyses of variability in levels of CDMs have the potential to bolster existing approaches for carcinogenicity testing.
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利用先进的测序技术研究癌症驱动基因突变的克隆扩增。
先进的测序技术(AST)彻底改变了癌症驱动突变(CDMs)作为罕见事件的定量研究,这在临床肿瘤学、癌症研究和癌症风险评估中都很有用。本综述将重点介绍利用 AST 来描述携带 CDMs 的细胞的克隆扩增(CE)特征并解释形成 CE 的选择性压力的研究。重要的是,高灵敏度的 AST 使突变克隆和组织学正常组织样本中的 CE 的特征描述成为可能,为研究新生肿瘤的发展提供了手段。有些 AST 能在空间定义的环境中识别突变克隆;有些 AST 则能将突变数据与基因表达分析相结合,从而阐明免疫、炎症、代谢和/或基质微环境对 CE 的影响。总体而言,这些研究清楚地表明,组织学上正常的组织中有很大一部分细胞携带 CDMs,CDMs 可能赋予特定环境的选择性优势,从而导致 CE,而只有一小部分携带 CDMs 的细胞最终导致肿瘤。这些观察结果与有关克隆选择机制的现有文献相结合,解释了如何将CDMs和CE的测量结果解释为癌症风险的生物标志物。鉴于癌变的随机性、驱动突变的潜在功能潜伏性、潜在突变与微环境相互作用的复杂性以及其他类型遗传和表观遗传变化的参与,得出的结论是,基于 CDM 的测量结果应被视为概率生物标志物,而非确定性生物标志物。CDM 水平样本间变异性的增加(CE 的结果)可能被解释为偏离正常组织稳态的转变和未来癌症风险增加的迹象,这一过程可能反映正常衰老或致癌物暴露。因此,对 CDM 水平变异性的分析有可能加强现有的致癌性测试方法。
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来源期刊
CiteScore
12.20
自引率
1.90%
发文量
22
审稿时长
15.7 weeks
期刊介绍: The subject areas of Reviews in Mutation Research encompass the entire spectrum of the science of mutation research and its applications, with particular emphasis on the relationship between mutation and disease. Thus this section will cover advances in human genome research (including evolving technologies for mutation detection and functional genomics) with applications in clinical genetics, gene therapy and health risk assessment for environmental agents of concern.
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