Whole-genome sequencing of biliary tract cancer: Uncovering the genomic origins of evolutionary trajectories.
Bibliographic record
Abstract
4116 Background: Biliary tract cancers (BTC) are rare, highly aggressive malignancies with limited treatment options, leading to consistently poor outcomes. An improved understanding of BTC tumor evolution could inform enhanced screening strategies, identify useful prognostic markers, and discover novel therapeutic targets. Methods: We performed whole genome and transcriptome sequencing (WGTS) at high depth ( > 80X) on a prospective cohort of BTC tumors. After detecting mutations and mutational signatures, we developed two novel methods for driver identification and evolutionary reconstruction. First, we created new oncogene and tumor suppressor-specific models that integrate copy number profiles, structural variant breakends, and expression changes to distinguish structural drivers from neutral chromosomal rearrangements. Second, we applied population genetics techniques to fit demographic models to tumor allele frequencies across 20 paired primary and metastatic samples. Results: We analyzed 130 tumor samples from 110 patients, representing the largest BTC whole-genome cohort to date. We identified hypermutated tumors (50-150 mutations/mb) with distinct etiologies, including mismatch repair deficiency, platinum exposure, tobacco use, and aristolochic acid-related damage, the latter of which was associated with response to immunotherapy. Ourintegrated-driver approach identified an association between selection on RAD23A and an increased structural variant load, resulting in a tandem-duplicator-like mutational phenotype. This also revealed an underappreciated impact of SMAD4 in BTC, which is inactivated through multiple mutation types in 12%. Notably, BAP1 mutations occurred in 24% of cases, including 4% that were inactivated through deletion of the BAP1 promoter that lowered transcript expression, a previously undescribed mechanism. By pairing clinical data to the genomics, we observed a co-occurrence of BAP1 mutations and FGFR2 fusions in small-duct, mass-forming intrahepatic cholangiocarcinomas. These mutations were mutually exclusive with TP53 mutations, which were enriched in patients with primary sclerosing cholangitis. Finally, our novel method for subclonal population reconstruction on paired samples illuminated recent tumor evolutionary dynamics and identified an ARID1B fusion with a potential role in metastasis. Conclusions: This study uncovered novel genomic mechanisms underlying the evolutionary origins of BTC beyond those previously identified with exome and panel sequencing, highlighting the value of WGTS. These results highlight the complex genomic heterogeneity of BTC, with potential implications for precision therapy.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
| 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 | 0.000 | 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".