Abstract B074: Clonal decomposition and DNA replication states defined by scaled single-cell DNA and RNA sequencing suggest clone-specific therapeutic vulnerabilities in neuroblastoma
Notice bibliographique
Résumé
Abstract Background: In neuroblastoma (NB), intratumor heterogeneity (ITH) is frequently observed, but the role of cell-to-cell allele-specific copy number alterations in phenotypic variation, clonal evolution and treatment response remains to be determined. Here we investigate ITH, timing of specific genomic aberrations, single-cell replication timing and the co-evolution of the genome and transcriptome in NB tumors at single-cell resolution, with an aim to analyse subclonal dynamics and clone-specific response or resistance under targeted therapeutic pressure. Methods: In addition to germline/tumor bulk whole exome sequencing (WES), ultra-low depth (0.25x) single-cell whole-genome DNA sequencing (scDNAseq) was performed using 10x genomics Chromium single-cell CNV (scCNV) kit and 9410 tumor cells were characterized from 14 patient-derived xenografts (PDX) NB-models and 4 tumor biopsies from NB-patients, either at diagnosis (n=7), progression (n=3) or relapse (n=8). Single-cell RNA sequencing (scRNAseq) data was obtained from the same PDX and patient tumor samples (Thirant et al, 2023). 6/14 PDX models were subjected to different treatment combinations (targeted treatment with/without chemotherapy) and bulk WES was performed at two time-points, pre- and post-treatment. Results: Both monoclonal (n=7) and polyclonal (n=11) genomes were determined by allele and haplotype specific copy number (CN) alteration using both scDNAseq and scRNAseq data analysis, with 2 to 11 clones observed per polyclonal NB tumor. Whole genome duplication events (n=7) were observed in both polyclonal and monoclonal genomes. Known driver CN (segmental loss in chr1p and chr11q and gain at chr17q, or MYCN/ALK amplification) or somatic mutations (ALK/ATRX/TP53/NF1) were early clonal events.Study of replication timing (RT) based on scDNAseq revealed significant differences in RT between the MYCN amplified (n=7) and non-amplified groups (n=5), with NB tumors without MYCN amplification (no MNA) characterized by a predominance of late replicating domains, in contrast to MYCN amplified (MNA) tumors, which are enriched in early replicating domains In a PDX model of interest, scDNAseq analysis showed parallel copy number evolution of two distinct clones, subclone s1/s2. Data integration of clonal mutational profiles with pre- and post-targeted therapy (Lorlatinib) revealed clone-specific treatment response. Subclone s2 was partially responding with extinction of a sub-set of somatic alterations, whereas no change was observed in subclone s1. The replication timing (RT) profile of these two clones, subclone s1 (early-RT) and s2 (late-RT) were mutually exclusive. Genotype to phenotype analysis revealed subclone s1 genotype was preferentially expressed at transcriptomic level. Conclusion: Together, these results determine the evolutionary trajectories of NB tumors, linked to distinct replication timing and highlight opportunities for targetable early clonal alteration detection. Citation Format: Jaydutt Bhalshankar, Angela Bellini, Irene Jimenez, Cécile Thirant, Elnaz Saberi-Ansari, Yasmine Iddir, Alexandra Saint Charles, Charlotte Butterworth, Amira Kramdi, Virginie Raynal, Sylvain Baulande, Didier Surdez, Sakina Zaidi, Gaelle Pierron, Angel Montero Carcaboso, Birgit Geoerger, Andrei Zinovyev, Olivier Delattre, Isabelle Janoueix-lerosey, Gudrun Schleiermacher. Clonal decomposition and DNA replication states defined by scaled single-cell DNA and RNA sequencing suggest clone-specific therapeutic vulnerabilities in neuroblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B074.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».