Circulating H3K27 Methylated Nucleosome plasma concentration: a synergistic information with ctDNA Molecular Profiling

Author:

Grolleau Emmanuel,Candiracci Julie,Lescuyer Gaelle,Barthelemy David,Benzerdjeb Nazim,Haon Christine,Geiguer Florence,Raffin Margaux,Hardat Nathalie,Balandier Julie,Rabeuf Rémi,Chalabreysse Lara,Wozny Anne-Sophie,Rommelaere Guillaume,Rodriguez-Lafrasse Claire,Subtil Fabien,Couraud Sébastien,Herzog Marielle,Payen-Gay Lea

Abstract

ABSTRACTBackgroundMolecular profiling of circulating tumor DNA (ctDNA) is a helpful tool for cancer treatment indication or for the early detection of relapse. A subset of patients with advanced lung adenocarcinoma cancers (NSCLC)can be cured by immunotherapy, radiotherapy, and/or chemotherapy combined regimens, or targeted therapies depending on their ctDNA molecular profile. However, clinical interpretation of ctDNA negative result remains challenging. Cell-free DNA (cfDNA) in association with nucleosomes are released into the bloodstream upon cell death therefore the characterization of both may provide useful information for patient management., Dysregulations of epigenetic modifications, such as histone methylation, are found to play a key role in tumorigenesis of different cancers. However, the concentration of circulating nucleosomes in blood, as a biomarker of the contributive value of ctDNA molecular profiling in patient management at diagnosis or during patient follow-up has not previously been investigated.ResultsSignificantly elevated concentrations of H3K27Me3-nucleosomes were found in plasmas at diagnosis and during the follow-up of NSCLC patients compared to healthy donors (median: 24ng/ml; 16.9ng/ml vs 8ng/ml, p-value<0.0001, respectively). Interestingly, by combining H3K27Me3 level and ctDNA molecular profile, we found that 25.5% of the patients had high levels of H3K27Me3 (above cut-off level at 22.5 ng/ml) and no somatic alteration detected at diagnosis. This strongly supports the presence of non-mutated ctDNA in the corresponding plasma. During patient follow-up, H3K27Me3 level was lower in ctDNA-negative group compared to ctDNA-positive group (medianctDNA-= 13.4 ng/mL vs medianctDNA+ = 26.1 ng/mL, respectively, p_value<0.0001). In 41.8% of the samples, no somatic mutation and low level of H3K27Me3-nucleosomes were observed suggesting molecular indicator of treatment response. In contrast, high H3K27Me3-nucleosome level was found in 15.1% of the sample despite no somatic mutations being detected allowing the identification of disease progression from 43.1% to 58.2% over molecular profiling alone.ConclusionMeasuring H3K27Me3-nucleosome levels in combination with ctDNA molecular profiling may not only improve confidence in the negative molecular result in cfDNA in lung cancer at diagnosis, it may also be a promising biomarker for Molecular Residual Disease (MRD) monitoring during and/or after treatment.

Publisher

Cold Spring Harbor Laboratory

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3