海报库PosterKeep
PO.BCS01.09 · 生物信息与计算

神经母细胞瘤的多组学分析鉴定出与较高复发风险相关的免疫学生物标志物：MICCHADO研究结果

Multi-omics profiling of neuroblastoma identifies immunological biomarkers associated with higher risk of relapse: Results from the MICCHADO study

海报缩略图：神经母细胞瘤的多组学分析鉴定出与较高复发风险相关的免疫学生物标志物：MICCHADO研究结果
编号 1469 展板 8 时间 4/20 09:00–12:00 区域 Section 5 主讲 Gudrun Schleiermacher, MD;PhD
分会场 Integrative Computational Approaches 1
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作者与单位 Authors & Affiliations

Antonio Colaprico1, Alexandra Saint-Charles1, Stelly Ballet2, Charles Bobin1, Joffrey Alves-Gasnier1, Valery Attignon3, Nathalie Droin1, Ana Lalanne4, Doriane Gorret4, Lydie Cassard5, Imene Hezam6, Yasmine Iddir1, Anthony Ferrari7, Elnaz Saberi Ansari1, Gaëlle Pierron2, Julien Masliah-Planchon2, Angela Bellini1, Nathalie Chaput5, Charlotte Butterworth1, Benoit Dumont3, Olivier Lantz4, Olivier Delattre1, Nadège Corradini3, Claudia Pasqualini6, Gudrun Schleiermacher1

1SiRIC RTOP, Translational Research Department, Institut Curie, PSL Research University; Institut Curie-Research Center, INSERM U1330, Childrens’ ONCology rEseaRch uniT (CONCERT), Paris, France,2Unité de Génétique Somatique, Department of Genetics, Institut Curie Hospital, Paris,France., Paris, France,3Department of Pediatric Oncology, Institut d'Hematologie et d'Oncologie Pédiatrique/Centre Léon Bérard, Lyon, France; Platform of Cancer Genomics, Centre Léon Bérard, Lyon, France,4Laboratory of Clinical Immunology, Department of Diagnostic and Theranostic Medicine, Institut Curie, Paris, France; Centre d'investigation Clinique en Biothérapie Gustave-Roussy Institut Curie (CIC-BT1428)., Paris, France,5Université Paris-Saclay, Gustave Roussy, AMMICa INSERM US23, Laboratoire d’immunomonitoring en Oncologie , F-94805, Villejuif, France,6INSERM US23, CNRS UMS 3655, Gustave Roussy, Villejuif, France; Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France,7Synergie Lyon Cancer, Gilles Thomas Bioinformatics Platform, Centre Léon Bérard, Lyon, France

摘要 Abstract

中文摘要
背景：神经母细胞瘤（NB）的风险分层依赖于临床和分子特征，尽管很少有分子标志物能指导治疗干预。借助多组学方法，我们试图鉴定与复发相关的生物标志物。 目的：刻画与高危NB（HR-NB，MYCN扩增或转移>12个月）复发相关的分子和免疫学特征，并将研究结果与临床结局相关联，以鉴定复发机制和治疗机会。 方法：对MICCHADO项目（NCT03496402，一个600例儿科患者的泛癌队列）中的197例NB患者（145例HR-NB，52例低/中危），使用配对肿瘤/种系全外显子组测序（WES）、bulk RNA测序、序贯血浆游离DNA（cfDNA）分析以及FACS血液流式细胞术，对肿瘤和序贯血液样本进行分析。我们评估了DNA改变、转录组亚型、干性、免疫浸润和血液生物标志物。 结果：在HR-NB中，与非HR相比，诊断时观察到更高的cfDNA和ctDNA水平。除既往已知的遗传特征（包括MYCN、DDX1和NBAS扩增、拷贝数改变以及复发性SNV）外，序贯cfDNA分析在复发时鉴定出新的改变，包括ALK、RAS-MAPK或CDKN2A/B。转录组分析揭示HR-NB以及经历复发的患者具有更高的干性指数，提示诊断时较高的干性指数可能预测复发风险。对诊断样本RNAseq的免疫去卷积揭示，经历复发的患者具有更高水平的CD4+记忆T细胞，但自然杀伤（NK）细胞较低。外周血流式细胞术揭示，如预期般，年轻患者中T细胞更多，且从诊断到治疗和复发，CD3+、CD4+、CD8+ T细胞和NK细胞显著减少。 结论：NB的多组学分析鉴定出与复发相关的新免疫生物标志物。较高的干性指数提示肿瘤更未分化、更易复发。免疫分析揭示了T细胞和NK细胞的变化，凸显了在靶向治疗中整合分子和免疫分析的必要性。 关键词：神经母细胞瘤、复发、生物标志物、多组学、免疫分析
查看英文原文 English abstract
BACKGROUND: Neuroblastoma (NB) risk stratification relies on clinical and molecular features, though few molecular markers inform therapeutic interventions. Leveraging multi-omics approaches, we sought to identify biomarkers associated with relapse. AIMSTo characterize molecular and immunological features associated with relapse inhigh-risk NB (HR-NB), (MYCN-amplified or metastatic >12 months), and correlate findingswith clinical outcomes to identify relapse mechanisms and therapeutic opportunities. METHODS: For 197 NB patients (145 HR-NB, 52 low/intermediate-risk) in the MICCHADOprogram (NCT03496402, a 600-pediatric patients pancancer cohort), tumor and sequentialblood samples were analyzed using paired tumor/germline whole exome sequencing(WES), bulk RNA sequencing, sequential plasma cell-free DNA (cfDNA) analysis, and bloodflow cytometry by FACS. We assessed DNA alterations, transcriptomic subtypes,stemness, immune infiltration, and blood biomarkers. RESULTS: In HR-NB higher cfDNA and ctDNA levels were observed at diagnosis compared to non-HR. In addition to previously known genetic features (including MYCN, DDX1 and NBAS amplification, copy number alterations as well as recurrent SNVs), sequential cfDNA analyses identified novel alterations at relapse, including ALK, RAS-MAPK or CDKN2A/B. Transcriptomic profiling revealed a higher stemness index in HR-NB and in patients who experienced relapse, suggesting that a higher stemness index at diagnosis may predict relapse risk. Immune deconvolution of RNAseq from diagnostic samples revealed that patients who experienced relapse had higher levels of CD4+ memory T-cells, but lower natural killer (NK)Cells. Peripheral blood flow cytometry revealed, as expected, more T-cells in younger patients and a significant decrease in CD3+, CD4+, CD8+ T-cells, and NK cells from diagnosis to treatment and relapse. CONCLUSIONS: Multi-omics profiling of NB identified novel immune biomarkersassociated with relapse. A higher stemness index suggests more undifferentiated, relapse-prone tumors. Immune profiling revealed T-cell and NK cell changes, highlighting the need for integrated molecular and immune profiling in targeted therapies. Keywords: Neuroblastoma, Relapse, Biomarkers, Multi-Omics, Immune Profiling
利益披露 Disclosure
A. Colaprico, None.. A. Saint-Charles, None.. S. Ballet, None.. C. Bobin, None.. J. Alves-Gasnier, None.. V. Attignon, None.. N. Droin, None.. A. Lalanne, None.. D. Gorret, None.. L. Cassard, None.. I. Hezam, None.. Y. Iddir, None.. A. Ferrari, None.. E. Saberi Ansari, None.. G. Pierron, None.. J. Masliah-Planchon, None.. A. Bellini, None.. N. Chaput, None.. C. Butterworth, None.. B. Dumont, None.. O. Lantz, None.. O. Delattre, None.. N. Corradini, None.. C. Pasqualini, None.. G. Schleiermacher, None.

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