Detection of novel variant TMPRSS2 /ERG fusion transcripts suggests independent genomic alterations may underlie origin of multi-centric prostate cancer
Bibliographic record
Abstract
10029 Background: Most of the early successes in identifying chromosomal translocations in neoplasias came from the study of hematological malignancies and sarcomas, with limited evidence that consistent genomic rearrangements were present in epithelial malignancies. Recently it was reported that ∼75% of prostate cancers carry a genomic rearrangement leading to fusion of the TMPRSS2 locus to either the ERG or ETV1 genes (both ETS transcription factors). In the fusion gene, the androgen-sensitive promoter elements of TMPRSS2 are thought to mediate over-expression of these ETS transcription factors. Over-activity of the ETS family of transcription factors has been suggested to be involved in the transition from pre-neoplasia to carcinoma as they regulate genes involved in processes such as adhesion, motility, invasion and angiogenesis. Methods: Using both RT-PCR and FISH with published primers and BACs respectively we analyzed 15 samples of prostatic carcinoma from radical prostatectomies and sequenced a subset of the TMPRSS2/ERG fusions. Results: We have found ERG-TMPRSS2 fusion transcripts in 6 samples and no ETV1-TMPRSS2 fusions. Of the 6 fusion tumours, 5 were Gleason 7 and 1 was Gleason 9. Tumour stages ranged from T2a-T3b. One sample with multi-centric carcinoma exhibited 2 distinct in-frame rearrangements generating novel TMPRSS2 /ERG fusion transcripts. Variant I TMPRSS2/ERG transcript was 430 bp and it led to fusion of exons 1 and 2 of the TMPRSS2 gene with exons 5 and 6 of the ERG gene. Variant II TMPRSS2/ERG fusion transcript was slightly smaller at 350 bp and it led to fusion of exon 1 of the TMPRSS2 gene to exons 5 and 6 of the ERG gene. These novel transcripts appear to be smaller than the published fusion proteins but preliminary analysis suggests that all known regulatory and functional protein domains are maintained. Conclusions: The demonstration of two new TMPRSS2/ERG variant fusion transcripts in prostate cancer deserves further study to evaluate their functional impact and prognostic and pathological importance. Moreover the presence of two distinct transcripts within a single multi-centric tumor provides genomic evidence that independent clonal neoplasms can arise synchronously in prostate cancer. No significant financial relationships to disclose.
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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 | 0.001 | 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) | 0.002 | 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".