Abstract LB196: An atlas of accessible chromatin in advanced prostate cancer
Bibliographic record
Abstract
Abstract Although androgen deprivation therapy (ADT) and second-generation Androgen Receptor (AR) signaling inhibitors (ARSIs) extend the survival of patients with metastatic castration-resistant prostate cancer (mCRPC), these tumors almost inevitably progress on these therapies. Prolonged usage of ADT and/or ARSI is associated with the development of treatment-associated transcriptional subtypes distinguished by alterations that affect the activity of the AR and neuroendocrine (NE) genes. Genomic and transcriptomic distinctions between the mCRPC subtypes are emerging. However, relatively little is known about the epigenome of the mCRPC transcriptional subtypes. We hypothesized that epigenetic mechanisms drive lineage plasticity in mCRPC by changing chromatin accessibility at regulatory loci for transcription factors (TFs) that affect downstream gene activity. In this study, we produced high-resolution chromatin accessibility maps linked to lineage-specific TF binding by performing Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) on 70 mCRPC tissue biopsy samples from the SU2C/PCF West Coast Prostate Cancer Dream Team cohort. Here, we demonstrate that the global chromatin accessibility profile of mCRPC is unique and primarily correlated with the functional activity of AR. We comprehensively examined genome-wide TF occupancy signals in accessible chromatin regions and identified 203 TFs associated with mCRPC subtypes. Our findings indicated that different mCRPC subtypes exhibit a specific preference for certain TFs. The AR+NE- subtype showed a greater dependence on TFs, such as FOXA1, AR, and HOXB13, while the AR-NE+ subtype was more addicted to ASCL1 and NEUROD1. We found that a group of TFs including SP1, KLF5, and ZNF263 that bind to GC-rich sequences, are likely to play a major role in the regulation of the AR-NE- subtype. Most notably, we identified a potentially novel TF in prostate cancer, ZNF263, which is estimated to have a significant impact on gene activity in the AR-NE- subtype and may play a role in activating the targets of the MYC signaling pathway. Overall, our analysis of chromatin accessibility in mCRPC provides valuable insights into epigenetic changes that occur during mCRPC progression. Citation Format: Raunak Shrestha, Lisa N. Chesner, Meng Zhang, Stanley Zhou, Adam Foye, Arian Lundberg, Alana S. Weinstein, Martin Sjöström, Xiaolin Zhu, Thaidy Moreno-Rodriguez, Haolong Li, Joshi J. Alumkal, Rahul Aggarwal, Eric J. Small, Mathieu Lupien, David A. Quigley, Felix Y. Feng. An atlas of accessible chromatin in advanced prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB196.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.002 | 0.002 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.006 | 0.002 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".