Integrative analysis of <i>KRAS</i>-wildtype pancreatic ductal adenocarcinoma reveals unique similarities to extrahepatic cholangiocarcinoma.
Bibliographic record
Abstract
587 Background: Oncogenic driver mutations in KRAS represent a hallmark genomic event in approximately 90% of pancreatic adenocarcinoma (PDAC). For the remaining 10% of patients with KRAS wildtype (wt) PDAC, distinct driver mutations have been described, but their transcriptional landscape has not been reported. Here, we leverage sequencing data from the PanGen trial to provide a comprehensive characterization of advanced KRASwt PDAC. Methods: 63 patients with advanced PDAC received whole genome and transcriptome sequencing prior to treatment for metastatic disease as part of the PanGen trial (NCT02869802). Clinical features, somatic mutation data and gene expression patterns were compared between KRASwt and mutant groups. PDAC samples were contrasted with 77 other metastatic carcinoma (colorectal and cholangiocarcinoma) samples from the Personalized OncoGenomics trial (NCT0215562). KRAS wt-associated genes were further investigated using 3 additional PDAC cohorts (COMPASS NCT02750657, TCGA, and ICGC). Results: 9 of 63 (14%) samples were KRASwt, with an earlier median age at diagnosis (51.4 vs. 60.9 years; p=0.03). Clinical features, including diabetes, family history of malignancy, and location of primary tumor, were comparable. CA 19-9 at baseline was lower in the KRASwt group, with median 58 vs. 4900 U/mL in the KRAS-mutant group ( p=0.03). Patients with KRASwt PDAC showed increased overall survival in univariable ( p=0.0024) and multivariable ( p=0.0089) analyses. 6 of 9 (67%) KRASwt tumors had fusions involving NRG1 (n = 3), FGFR2 (n = 1), BRAF (n = 1) or NTRK2 (n = 1), while known actionable fusions were not observed in KRAS mutant patients. KRASwt tumors showed increased expression of genes associated with cholangiocytes and grouped with cholangiocarcinoma samples in unsupervised clustering analysis. Validation using three independent PDAC cohorts revealed a core set of 70 KRAS wt-associated genes that converge on keratinization, ion transport, and hormone metabolism pathways. Conclusions: Patients with KRASwt PDAC show potentially targetable molecular traits with actionable fusions. We also highlight novel mutation and expression-based similarities between KRASwt PDAC and cholangiocarcinoma samples. Recurrent dysregulation of genes involved in cellular structure and metastasis provide impetus for further investigation into the developmental trajectory and potential therapeutic vulnerabilities of KRASwt PDAC.
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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 | 0.000 | 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 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".