The prognostic value of mutational signatures in pancreatic cancer.
Bibliographic record
Abstract
689 Background: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor overall survival (OS), however there are significant outliers. Understanding the biological factors driving PDAC cancer may reveal new biomarkers and treatment strategies. Mutational signatures, imprinted in the cancer genome, encode the life history of the cancer and may be used to stratify tumors into clinically-relevant subgroups. Methods: In this study we performed mutational signature analysis (MutationalPatterns, COSMIC v3.3) on whole genomes from 434 PDAC patients, comprising 167 patients with resected primary tumors, and 267 advanced PDACs from patients enrolled in the COMPASS trial. We evaluated whether the mutational signatures detected associate with OS using the log-rank test in the overall cohort and stratified by disease stage, adjusting for multiple hypotheses with 5% false discovery rate (FDR). We further characterized these associations in exploratory analyses. Results: Among the 55 COSMIC signatures detected in the overall cohort, the presence of three signatures significantly associated with OS after FDR correction. SBS85, a signature associated with indirect effects of activation-induced cytidine deaminase, was present in 18/434 (4.1%) samples, and was significantly associated with improved OS in the overall study population (log-rank p=6.5e-4, FDR-adjusted-p=0.026). SBS93, a signature of unknown etiology previously seen in other gastrointestinal cancers, was present in 4/434 (0.9%) samples, and was significantly associated with worse OS in the overall study population (log-rank, p=7e-6; FDR-adjusted-p=1.1e-3). SBS33, also of unknown etiology and previously seen in other gastrointestinal cancers, was present in 73/434 (16.8%) samples. It was seen more frequently in advanced disease (Fisher’s-exact p=1.9e-4), but was significantly associated with worse OS only in the resected cohort (log-rank, p=2.3e-4, FDR-adjusted-p=0.012). Conclusions: We identified three mutational signatures—SBS85, SBS93, and SBS33—that have not previously been described in PDAC and associate with OS. Further characterization of these novel signatures in PDAC and their underlying biology may uncover new treatment avenues.
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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 | 0.001 | 0.002 |
| 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 | 0.001 |
| 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 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".