Abstract B006: Development of a NF1-MPNST-PDX liquid biopsy model using whole-genome sequencing and quantitative PCR of mouse-derived cell-free DNA
Notice bibliographique
Résumé
Abstract Background: Malignant Peripheral Nerve Sheath Tumors (MPNST) are aggressive, NF1-associated soft tissue sarcomas with a dismal 40% 5-year survival rate, high rates of disease relapse and metastasis, and limited treatment options. Our lab has generated a collection of patient-derived xenograft (PDX) models, which recapitulate the variety of genetic changes that occur in human NF1-MPNST. Longitudinal analysis of PDX tumor burden in preclinical studies is currently limited to imprecise tumor measurement or expensive and time-consuming imaging modalities such as MRI. These methods of analysis fail to allow for the early detection of tumor formation, the assessment of treatment-response dynamics, the formation of resistant subclones, or the detection of molecular residual disease. Liquid biopsies using plasma-derived cell-free DNA (cfDNA) have been successful in addressing these challenges in the context of multiple solid tumor types including MPNST by our group previously (Szymanski et al. 2021). However, liquid biopsy of cfDNA in the context murine model systems is quite limited, primarily due the challenge of collecting sufficient plasma for analysis. We hypothesize that we can detect and longitudinally track tumor burden in response to treatment using human-tumor-specific quantitative PCR (qPCR) and whole-genome sequencing of sequentially collected PDX-bearing murine plasma to develop a NF1-MPNST-PDX liquid biopsy model. Methods: To address this challenge, we sequentially collected ≈50 µL of murine plasma weekly from two independent groups of NF1-MPNST-PDX-bearing mice and corresponding PDX-free controls for up to six weeks. The first group consisted of six PDX-bearing mice who underwent whole-genome sequence of murine-derived plasma cfDNA and paired PDX tissue. The second group consisted of fifteen NF1-MPNST-PDX-bearing mice and five PDX-free controls; plasma cfDNA samples collected from this group underwent human-specific LINE-1 qPCR, which should only detect human DNA derived from implanted PDX and allow for longitudinal tracking of tumor burden. Results: We serially collected ≈50 µL of plasma weekly from NF1-MPNST-PDX mice with no obvious impact on mouse survival or weight. Mean total cfDNA yield from the terminally collected samples was 1.12 ± 1.02 ng per uL plasma (n=21) for PDX-bearing animals with cfDNA fragments canonically appearing between 70 and 450 bps as determined by electropherogram. Whole-genome sequencing of murine plasma cfDNA revealed broad genomic aneuploidy detectable in NF1-MPNST-PDX plasma which corresponded to alterations present in PDX tissue, including MPNST-specific chromosome 8q gain, corresponding with our earlier findings (Dehner et al. 2021). Human-specific LINE-1 qPCR showed specific enrichment of tumor-derived LINE-1 in NF1-MPNST-PDX-bearing mice compared to PDX-free mice which showed no human LINE-1 enrichment. Conclusion: Our data suggest that PDX plasma cfDNA may be an informative biomarker that can be non-invasively collected and used to track tumor burden in NF1-MPNST-PDX models. Citation Format: Paul A. Jones, Wenjia Feng, Xiaochun Zhang, Peter K. Harris, Taylor Sundby, Jeffrey J. Szymanski, Divya Srihari, Faridi Qaium, Jack F. Shern, Aadel A. Chaudhuri, Angela C. Hirbe. Development of a NF1-MPNST-PDX liquid biopsy model using whole-genome sequencing and quantitative PCR of mouse-derived cell-free DNA [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr B006.
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 | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,001 |
| Science ouverte | 0,001 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
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 ».