LINE1 elements are hijacking by genetic and epigenetic variation drives metastatic prostate cancer
Why this work is in the frame
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Bibliographic record
Abstract
This capsule integrates processed ATAC-seq, RNA-seq, WGS and HiC to identify enrichment of transposable elements in accessible chromatin and their activation as regulatory elements bound by oncogenic transcription factors. Abstract Prostate cancer remains a fatal disease for patients who progress to metastatic castration-resistant prostate cancer (mCRPC) after first-line curative-intent therapies. While genetic subtypes are reported for mCRPCs, recent evidence points to non-genetic variants within the repetitive genome as critical drivers of prostate tumor development. Integrating chromatin accessibility, whole-genome sequencing, and Hi-C-based genome topology data from the West coast dream team (WCDT) mCRPC cohort, we identify four mCRPC subgroups characterized by chromatin variants over the repetitive genome revealing hijacking of transposable elements. Among these, the LINE1+ subgroup representing 20% of the samples is characterized by clusters of LINE1 transposable elements flanking the androgen receptor (AR) gene that are co-amplified locally or in extrachromosomal circular DNA (ecDNA) and preferentially become accessible. The synchronicity of these non-genetic and genetic variants on LINE1 transposable elements leads to their co-option as binding sites for prostate-lineage transcription factors, including AR and its cofactors FOXA1, HOXB13, and GATA2. Accessible LINE1 elements create a subgroup-specific regulatory plexus to drive AR overexpression, conferring resistance to AR signaling inhibitors (ARSI). These findings establish the convergence of genetic and epigenetic variations affecting the repetitive genome as a defining feature of mCRPC classification, identifying LINE1+ mCRPCs as a mechanistically distinct and clinically refractory entity, and underscoring the pivotal role of transposable elements in shaping advanced prostate cancer biology.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 it