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下一代测序技术在卵巢癌血浆循环肿瘤DNA中的当前应用与挑战

Current Applications and Challenges of Next-Generation Sequencing in Plasma Circulating Tumour DNA of Ovarian Cancer.

作者信息

Roque Ricardo, Ribeiro Ilda Patrícia, Figueiredo-Dias Margarida, Gourley Charlie, Carreira Isabel Marques

机构信息

Cytogenetics and Genomics Laboratory, Institute of Cellular and Molecular Biology, Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.

Centre of Investigation on Environment Genetics and Oncobiology (CIMAGO), Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, 3004-504 Coimbra, Portugal.

出版信息

Biology (Basel). 2024 Jan 31;13(2):88. doi: 10.3390/biology13020088.

Abstract

Circulating tumour DNA (ctDNA) facilitates longitudinal study of the tumour genome, which, unlike tumour tissue biopsies, globally reflects intratumor and intermetastatis heterogeneity. Despite its costs, next-generation sequencing (NGS) has revolutionised the study of ctDNA, ensuring a more comprehensive and multimodal approach, increasing data collection, and introducing new variables that can be correlated with clinical outcomes. Current NGS strategies can comprise a tumour-informed set of genes or the entire genome and detect a tumour fraction as low as 10. Despite some conflicting studies, there is evidence that ctDNA levels can predict the worse outcomes of ovarian cancer (OC) in both early and advanced disease. Changes in those levels can also be informative regarding treatment efficacy and tumour recurrence, capable of outperforming CA-125, currently the only universally utilised plasma biomarker in high-grade serous OC (HGSOC). Qualitative evaluation of sequencing shows that increasing copy number alterations and gene variants during treatment may correlate with a worse prognosis in HGSOC. However, following tumour clonality and emerging variants during treatment poses a more unique opportunity to define treatment response, select patients based on their emerging resistance mechanisms, like BRCA secondary mutations, and discover potential targetable variants. Sequencing of tumour biopsies and ctDNA is not always concordant, likely as a result of clonal heterogeneity, which is better captured in the plasma samples than it is in a large number of biopsies. These incoherences may reflect tumour clonality and reveal the acquired alterations that cause treatment resistance. Cell-free DNA methylation profiles can be used to distinguish OC from healthy individuals, and NGS methylation panels have been shown to have excellent diagnostic capabilities. Also, methylation signatures showed promise in explaining treatment responses, including BRCA dysfunction. ctDNA is evolving as a promising new biomarker to track tumour evolution and clonality through the treatment of early and advanced ovarian cancer, with potential applicability in prognostic prediction and treatment selection. While its role in HGSOC paves the way to clinical applicability, its potential interest in other histological subtypes of OC remains unknown.

摘要

循环肿瘤DNA(ctDNA)有助于对肿瘤基因组进行纵向研究,与肿瘤组织活检不同,它能全面反映肿瘤内和转移灶间的异质性。尽管成本高昂,但二代测序(NGS)彻底改变了ctDNA的研究方式,确保了更全面和多模式的方法,增加了数据收集,并引入了可与临床结果相关联的新变量。当前的NGS策略可以包括一组肿瘤相关基因或整个基因组,并能检测低至1%的肿瘤比例。尽管有一些相互矛盾的研究,但有证据表明,ctDNA水平可以预测早期和晚期卵巢癌(OC)的不良预后。这些水平的变化也可以提供有关治疗效果和肿瘤复发的信息,其表现优于CA-125,CA-125是目前高级别浆液性卵巢癌(HGSOC)中唯一普遍使用的血浆生物标志物。测序的定性评估表明,治疗期间拷贝数改变和基因变异的增加可能与HGSOC的预后较差相关。然而,追踪治疗期间的肿瘤克隆性和新出现的变异提供了一个更独特的机会来定义治疗反应,根据患者新出现的耐药机制(如BRCA二次突变)选择患者,并发现潜在的可靶向变异。肿瘤活检和ctDNA的测序结果并不总是一致的,这可能是由于克隆异质性导致的,血浆样本比大量活检样本能更好地捕捉到这种异质性。这些不一致可能反映肿瘤克隆性,并揭示导致治疗耐药的获得性改变。游离DNA甲基化谱可用于区分OC患者和健康个体,并且NGS甲基化检测板已被证明具有出色的诊断能力。此外,甲基化特征在解释治疗反应(包括BRCA功能障碍)方面显示出前景。ctDNA正在成为一种有前景的新型生物标志物,可通过对早期和晚期卵巢癌的治疗来追踪肿瘤演变和克隆性,在预后预测和治疗选择中具有潜在的应用价值。虽然其在HGSOC中的作用为临床应用铺平了道路,但其在OC其他组织学亚型中的潜在价值仍不清楚。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/80c8/10886635/364c269921fc/biology-13-00088-g001.jpg

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