Whole-genome sequencing of 20 cholangiocarcinoma cases reveals unique profiles in patients with cirrhosis and primary sclerosing cholangitis
Bibliographic record
Abstract
Background: Cholangiocarcinoma (CCA) is a molecularly heterogenous disease that is often fatal. Whole genome sequencing (WGS) can provide additional knowledge of mutational spectra compared with panel sequencing. We describe the molecular landscape of CCA using whole-genome sequencing and compare the mutational landscape between short-term and long-term survivors. Methods: We explored molecular differences between short-term and long-term survivors by performing WGS on 20 patient samples from our biliary tract cancer database. Short-term survivors were enriched for cases with underlying primary sclerosing cholangitis (PSC) and patients with cirrhosis. All samples underwent tumour epithelial enrichment using laser capture microdissection (LCM). Results: Dominant single base substitution (SBS) signatures across the cohort included SBS1 and SBS5, with the latter more prevalent in long-term survivors. SBS17 was evident in 3 cases, all of whom had underlying ulcerative colitis (UC) with PSC. Additional rare signatures included SBS3 in a patient treated for prior mantle cell lymphoma and SBS26/SBS6 in a patient with a tumor mutational burden of 33 mutations/Mb and a pathogenic MLH1 germline mutation. Somatic TP53 inactivating mutations were present in 8/10 (80%) short-term survivors and in none of the long-term survivors. Additional mutations occurred in KRAS, SMAD4, CDKN2A, and chromatin remodelling genes. The long-term survivor group harboured predicted fusions in FGFR (n=2) and pathogenic mutations in BRAF and IDH1 (n=2). Conclusions: TP53 alterations are associated with poor outcomes in patients with CCA. Patients with underlying inflammatory/autoimmune conditions may be enriched for unique tumour mutational signatures.
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How this classification was reachedexpand
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) | 0.001 | 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) | 0.000 | 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".