Abstract 1985: 5hmC-sequencing of matched cfDNA and tissue from men with mCRPC is concordant and identifies loss of AR signaling in NEPC and DNPC
Notice bibliographique
Résumé
Abstract Purpose: In this study, we aimed to study whether 5-hydroxymethylcytosine sequencing (5hmC-seq) of circulating cell-free DNA (cfDNA) predicts gene expression in tumor tissue and can distinguish tumor subtypes defined in tissue in metastatic castration-resistant prostate cancer (mCRPC). Methods: We performed 5hmC-seq on cfDNA samples from 86 mCRPC patients with matched tumor tissue profiled with 5hmC-seq (N=49) and RNA-sequencing (N=86) and we compared cfDNA 5hmC levels with matched tissue 5hmC levels and tissue gene expression. We developed a 5hmC-seq-based circulating tumor-DNA fraction (ctDNA-fraction) classifier and assessed if gene-level and pathway-level differences between mCRPC subtypes could be detected in cfDNA using a differential 5hmC-analysis adjusting for ctDNA-fraction. Results: Patients with androgen receptor (AR)-positive prostate cancer (ARPC) exhibited lower ctDNA-fraction, whereas patients with neuroendocrine (NE) prostate cancer (NEPC) and double-negative prostate cancer (DNPC) tumors displayed higher ctDNA-fraction (median ctDNA-fraction across subtypes 0.09 [95% confidence interval (CI), 0.04-0.14] (ARPC), 0.41 [95% CI, 0.18-0.64] (NEPC) and 0.37 [95% CI, 0.30-0.44] (DNPC), pairwise t-test P = 5.5 x 10-2 (ARPC vs. NEPC) and P = 8.8 x 10-4 (ARPC vs. DNPC) respectively). Nearly 30% of all protein-coding genes showed significant concordance between cfDNA 5hmC and tissue RNA-seq, after adjusting for ctDNA-fraction (adjusted p<0.05 in linear model), which were enriched in the androgen response, EGFR, and ERBB signaling pathways. Compared to ARPC, NEPC displayed upregulated 5hmC enrichment in NE-related genes, and downregulated androgen response and MYC target pathways in cfDNA. As expected, an NE pathway score calculated from cfDNA 5hmC was significantly different between tissue-confirmed ARPC and NEPC (p=0.03). Double-negative prostate cancer (DNPC) showed downregulated androgen response and MYC targets and upregulated epithelial cell pathways compared to ARPC in cfDNA. Furthermore, DNPC indicated an aggressive phenotype with cell proliferation pathways even more upregulated when compared to NEPC. Conclusions: We created a cohort of 86 matched tissue and cfDNA samples and demonstrated concordance for a significant number of transcribed protein-coding genes. Expected biological differences previously seen in tissue between NEPC and ARPC were readily detected via 5hmC profiles in cfDNA. Furthermore, DNPC showed a clear downregulation of androgen response signaling in cfDNA, indicating the possibility to identify a group of patients in addition to classical NEPC that may have reduced response to standard androgen-targeting agents. Future work will aim to develop single-sample multi-class subtype classifiers and evaluate differences in prognosis and treatment response based on cfDNA-based subtyping. Citation Format: Rensheng Wan, Raunak Shrestha, Gulfem Guler, Yuhong Ning, Aishwarya Subramanian, Adam Foye, Meng Zhang, Xiaolin Zhu, Thaidy Moreno-Rodriguez, Haolong Li, Shuang G. Zhao, SU2C/PCF West Coast Prostate Cancer Dream Team, Joshi J. Alumkal, Rahul Aggarwal, Alexander W. Wyatt, David Quigley, Samuel Levy, Eric Small, Felix Feng, Martin Sjöström. 5hmC-sequencing of matched cfDNA and tissue from men with mCRPC is concordant and identifies loss of AR signaling in NEPC and DNPC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1985.
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 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 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 | 0,000 | 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 ».