Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy.
Clinically Relevant and Minimally Invasive Tumor Surveillance of Pediatric Diffuse Midline Gliomas Using Patient-Derived Liquid Biopsy.
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DOI：
10.1158/1078-0432.ccr-18-1345
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发表时间：
2018-12-01
期刊：
影响因子：
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通讯作者：
Nazarian J
中科院分区：
文献类型：
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作者：
Panditharatna E;Kilburn LB;Aboian MS;Kambhampati M;Gordish-Dressman H;Magge SN;Gupta N;Myseros JS;Hwang EI;Kline C;Crawford JR;Warren KE;Cha S;Liang WS;Berens ME;Packer RJ;Resnick AC;Prados M;Mueller S;Nazarian J
儿童DMG是高度恶性的肿瘤，临床结局较差。超过70%的DMG患者携带组蛋白3 p.K27M（H3 K27 M）突变，这与较差的临床结局相关，也被用作临床试验的入选标准。由于DMG的完全手术切除不是一种选择，在表现时活检是可行的，但在进展时再次活检是罕见的。虽然成像和基于临床的疾病监测是护理标准，但这些肿瘤的基于分子的纵向表征几乎不存在。为了克服这些障碍，我们检查了液体活检是否可以测量疾病对精确治疗的反应。我们建立了一种灵敏和特异的方法，使用液滴数字PCR检测与儿科DMG相关的主要驱动突变（n=48例受试者，n=110份标本）。与集中审查的MRI数据相比，H3 K27 M的ctDNA定量用于疾病反应的纵向评估。在88%的DMG患者的脑脊液（CSF）和血浆中鉴定出H3 K27 M，其中CSF最富集ctDNA。我们证明了多重检测H3 K27 M的可行性，以及患者肿瘤和匹配CSF中的额外驱动突变，最大化液体生物组的单一来源的效用。H3 K27 M血浆ctDNA的显著降低与83%（10/12）的患者中肿瘤对放疗的反应的MRI评估一致。我们的液体活检方法为肿瘤表征提供了基于分子的工具，并且是第一个表明ctDNA用于DMG纵向监测的临床实用性的方法。
Pediatric DMGs are highly malignant tumors with poor clinical outcomes. Over 70% of DMG patients harbor the histone 3 p.K27M (H3K27M) mutation, which correlates with a poorer clinical outcome, and is also used as a criterion for enrollment in clinical trials. Because complete surgical resection of DMG is not an option, biopsy at presentation is feasible, but re-biopsy at time of progression is rare. While imaging and clinical-based disease monitoring is the standard of care, molecular-based longitudinal characterization of these tumors is almost non-existent. To overcome these hurdles we examined if liquid biopsy allows measurement of disease response to precision therapy. We established a sensitive and specific methodology which detects major driver mutations associated with pediatric DMGs using droplet digital PCR (n=48 subjects, n=110 specimens). Quantification of ctDNA for H3K27M was used for longitudinal assessment of disease response compared to centrally reviewed MRI data. H3K27M was identified in cerebrospinal fluid (CSF) and plasma in 88% of patients with DMG, with CSF being the most enriched for ctDNA. We demonstrated the feasibility of multiplexing for detection of H3K27M, and additional driver mutations in patient’s tumor and matched CSF, maximizing the utility of a single source of liquid biome. A significant decrease in H3K27M plasma ctDNA agreed with MRI assessment of tumor response to radiotherapy in 83% (10/12) of patients. Our liquid biopsy approach provides a molecularly-based tool for tumor characterization, and is the first to indicate clinical utility of ctDNA for longitudinal surveillance of DMGs.