Repertoire and clinical hierarchy of AR locus alterations in castration-resistant prostate cancer
Bibliographic record
Abstract
BACKGROUND: Somatic alterations to the androgen receptor (AR) gene are pivotal drivers of treatment resistance in metastatic castration-resistant prostate cancer (mCRPC), but their prevalence, clinical impact, and etiology remain incompletely understood. PATIENTS AND METHODS: We assembled a meta-cohort of 3048 plasma cell-free DNA and matched leukocyte DNA samples from 1751 mCRPC patients, accrued from eight clinical trials and a regional biobank. Samples were sequenced with successive generations of a custom targeted hybridization capture panel with extensive coverage of the AR locus and 71 prostate cancer genes, enabling comprehensive characterization of AR genotypes including enhancer and gene copy number amplification, and mutations or structural rearrangements. RESULTS: Somatic AR alterations, detected in 84% of mCRPC, were shaped by underlying genomics, including TP53 and DNA repair defects. Wnt-mutant tumors showed unique AR amplification structures characterized by preferential incorporation of an alternative downstream enhancer and low copy number. AR mutations were present in 19.7% of mCRPC, often subclonal, and enriched in tumors with AR enhancer-only gain. We establish a functional hierarchy of AR genotypes based on treatment responses and identify a specific class of AR rearrangements truncating the ligand-binding domain within intron 4 or exon 4 (ALTR4) that are under robust positive selection and strongly impact AR pathway inhibitor outcomes, distinct from other rearrangements arising as byproducts of AR amplification. We provide evidence that a subset of AR amplifications arise through breakage-fusion-bridge cycles with associated Xq loss. Some 16% of mCRPC lacked detectable AR alterations and had reduced frequency of ETS gene fusions, with many demonstrating robust responses to AR pathway inhibitors. CONCLUSIONS: This study provides the most comprehensive resource to date characterizing somatic alterations at the AR locus. Our clinicogenomic analysis establishes the repertoire and clinical relevance of AR genotypes in mCRPC, informing efforts to target renewed AR dependency.
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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 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
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".