Gene expression signatures of neuroendocrine prostate cancer and primary small cell prostatic carcinoma
Why this work is in the frame
A frame that forgets how it found something cannot be audited. These are the routes that admitted this work.
Bibliographic record
Abstract
BACKGROUND: Neuroendocrine prostate cancer (NEPC) may be rising in prevalence as patients with advanced prostate cancer potentially develop resistance to contemporary anti-androgen treatment through a neuroendocrine phenotype. While prior studies comparing NEPC and prostatic adenocarcinoma have identified important candidates for targeted therapy, most have relied on few NEPC patients due to disease rarity, resulting in thousands of differentially expressed genes collectively and offering an opportunity for meta-analysis. Moreover, past studies have focused on prototypical NEPC samples with classic immunohistochemistry profiles, whereas there is increasing recognition of atypical phenotypes. In the primary setting, small cell prostatic carcinoma (SCPC) is frequently admixed with adenocarcinomas that may be clonally related, and a minority of SCPCs express markers typical of prostatic adenocarcinoma while rare cases do not express neuroendocrine markers. We derived a meta-signature of prototypical high-grade NEPC, then applied it to develop a classifier of primary SCPC incorporating disease heterogeneity. METHODS: Prototypical NEPC samples from 15 patients across 6 frozen tissue microarray datasets were assessed for genes with consistent outlier expression relative to adenocarcinomas. Resulting genes were used to determine subgroups of primary SCPCs (N=16) and high-grade adenocarcinomas (N=16) profiled by exon arrays using formalin-fixed paraffin-embedded (FFPE) material from our institutional archives. A subgroup classifier was developed using differential expression for feature selection, and applied to radical prostatectomy cohorts. RESULTS: Sixty nine and 375 genes demonstrated consistent outlier expression in at least 80% and 60% of NEPC patients, with close resemblance in expression between NEPC and small cell lung cancer. Clustering by these genes generated 3 subgroups among primary samples from our institution. Nearest centroid classification based on the predominant phenotype from each subgroup (9 prototypical SCPCs, 9 prototypical adenocarcinomas, and 4 atypical SCPCs) achieved a 4.5% error rate by leave-one-out cross-validation. The classifier identified SCPC-like expression in 40% (2/5) of mixed adenocarcinomas and 0.3-0.6% of adenocarcinomas from prospective (4/2293) and retrospective (2/355) radical prostatectomy cohorts, where both SCPC-like retrospective cases subsequently developed metastases. CONCLUSIONS: Meta-analysis generates a robust signature of prototypical high-grade NEPC, and may facilitate development of a primary SCPC classifier based on FFPE material with potential prognostic implications.
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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) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 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) | 0.000 | 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