Detection of H3F3A K27M or BRAF V600E in liquid biopsies of brain tumor patients as diagnostic and monitoring biomarker: impact of tumor localization and sampling method

IF 9.3 1区医学 Q1 CLINICAL NEUROLOGY

Acta Neuropathologica Pub Date : 2025-01-03 DOI:10.1007/s00401-024-02842-7

Sibylle Madlener, Natalia Stepien, Daniel Senfter, Lisa Mayr, Anna Laemmerer, Cora Hedrich, Alicia Baumgartner, Daniela Lötsch-Gojo, Jaroslav Sterba, Petra Pokorna, Barbara Kiesel, Georg Widhalm, Franziska Eckert, Matthias Preusser, Karl Rössler, Amedeo Azizi, Andreas Peyrl, Thomas Czech, Christine Haberler, Irene Slavc, Gregor Kasprian, Christian Dorfer, Julia Furtner, Johannes Gojo

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引用次数: 0

Abstract

Gliomas are the most common brain tumor type in children and adolescents. To date, diagnosis and therapy monitoring for these tumors rely on magnetic resonance imaging (MRI) and histopathological as well as molecular analyses of tumor tissue. Recently, liquid biopsies (LB) have emerged as promising tool for diagnosis and longitudinal tumor assessment potentially allowing for a more precise therapeutic management. However, the optimal strategy for monitoring gliomas by LB remains to be determined. In this study, we analyzed circulating tumor DNA (ctDNA) from 78 liquid biopsies (plasma n = 44, cerebrospinal fluid n = 34 (CSF)) of 35 glioma patients, determining H3F3A K28M (K27M) and BRAF V600E mutation allele frequency using droplet digital PCR (ddPCR). All results were correlated to clinically relevant parameters including diagnostic imaging and CSF aspiration site (ventricular vs lumbar) with respect to tumor localization. Regarding diagnostic accuracy, the calculated sensitivity score in the H3F3A K27M cohort was 84.61% for CSF and 73.68% for plasma. In the BRAF V600E cohort, we determined a sensitivity of 83.3% in plasma and 80% in CSF. The overall specificity was 100%. With respect to the CSF aspiration, the intra-operatively obtained CSF demonstrated 100% detection rate, followed by ventricular CSF obtained via Ommaya Reservoir/shunt puncture (93%) and CSF obtained via lumbar puncture (66%). Notably, this further correlated with the proximity of the CSF site to tumor localization. Longitudinal CSF monitoring demonstrated a good correlation to clinical and radiological disease evolution. Importantly, we show for the first time that monitoring BRAF V600E by ddPCR could serve as treatment response assessment in gliomas. In summary, our observation may inform recommendations with regard to location of CSF aspiration when incorporating LB into future treatment protocols.

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脑肿瘤患者液体活检中检测H3F3A K27M或BRAF V600E作为诊断和监测生物标志物：肿瘤定位和采样方法的影响

胶质瘤是儿童和青少年中最常见的脑肿瘤类型。迄今为止，这些肿瘤的诊断和治疗监测依赖于磁共振成像（MRI）和组织病理学以及肿瘤组织的分子分析。最近，液体活检（LB）已成为诊断和纵向肿瘤评估的有前途的工具，可能允许更精确的治疗管理。然而，通过LB监测胶质瘤的最佳策略仍有待确定。本研究对35例胶质瘤患者的78份液体活检（血浆44份，脑脊液34份）的循环肿瘤DNA （ctDNA）进行分析，采用液滴数字PCR （ddPCR）测定H3F3A K28M （K27M）和BRAF V600E突变等位基因频率。所有结果均与临床相关参数相关，包括诊断成像和脑脊液吸入部位（脑室vs腰椎）与肿瘤定位。在诊断准确性方面，H3F3A K27M队列计算敏感性评分CSF为84.61%，血浆为73.68%。在BRAF V600E队列中，我们确定血浆和脑脊液的敏感性分别为83.3%和80%。总体特异性为100%。术中采集的脑脊液检出率为100%，其次是经Ommaya储液池/分流穿刺采集的脑脊液（93%）和经腰椎穿刺采集的脑脊液（66%）。值得注意的是，这进一步与脑脊液部位靠近肿瘤定位相关。纵向脑脊液监测显示与临床和放射学疾病发展有良好的相关性。重要的是，我们首次表明，通过ddPCR监测BRAF V600E可以作为胶质瘤治疗反应的评估。综上所述，我们的观察结果可以为今后将LB纳入治疗方案时脑脊液抽吸位置的建议提供参考。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Neuropathologica 医学-病理学

CiteScore

23.70

自引率

3.90%

发文量

118

审稿时长

4-8 weeks

期刊介绍： Acta Neuropathologica publishes top-quality papers on the pathology of neurological diseases and experimental studies on molecular and cellular mechanisms using in vitro and in vivo models, ideally validated by analysis of human tissues. The journal accepts Original Papers, Review Articles, Case Reports, and Scientific Correspondence (Letters). Manuscripts must adhere to ethical standards, including review by appropriate ethics committees for human studies and compliance with principles of laboratory animal care for animal experiments. Failure to comply may result in rejection of the manuscript, and authors are responsible for ensuring accuracy and adherence to these requirements.