Urothelial Bladder Carcinomas with High Tumor Mutation Burden Have a Better Prognosis and Targetable Molecular Defects beyond Immunotherapies
Bibliographic record
Abstract
Background: Urothelial bladder carcinomas had traditionally been difficult to treat cancers, with high morbidity and mortality rates when invasive and metastatic. In recent years, immunotherapy with immune checkpoint inhibitors has improved outcomes in several cancers, including bladder carcinomas. Despite positive overall results, many bladder cancer patients do not respond to immunotherapies. Validated predictive biomarkers of response would advance the selection of patients for these treatments. Tumor mutation burden (TMB) has been suggested as an immunotherapy biomarker and thus delineation of attributes of tumors with a high TMB is clinically relevant. Methods: Publicly available genomic and clinical data from the urothelial bladder carcinoma cohort of The Cancer Genome Atlas (TCGA) project are used to analyze characteristics and molecular alterations of the subset of cancers with an increased tumor mutation number compared with those with lower number of mutations. The cut-off for the high mutation burden in the analysis was set at 10 mutations per Megabase (MB). Results: In addition to their sensitivity to immune checkpoint inhibitors, urothelial carcinomas with high TMB possess several molecular defects that could be exploited for combinatorial treatments. Compared with bladder carcinomas with low TMB, carcinomas with high TMB display higher prevalence of mutations in tumor suppressor TP53, PIK3CA, in FAT4 cadherin and in genes encoding for several epigenetic modifier enzymes. The frequency of mutations in mismatch repair and DNA damage response genes is higher in cancers with high TMB. The group of urothelial carcinomas with high TMB has a better prognosis than the group with low TMB. This improved Overall Survival (OS) stems from improved survival of stage III cancers with high TMB compared with stage III cancers with low TMB, while stage II and stage IV cancers have similar OS, independently of their TMB. Conclusion: Differences of the landscape of high and low TMB urothelial cancers provides leads for further pathogenesis investigations and may prove useful for development of combination therapies including immunotherapies with targeted inhibitors.
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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) | 0.000 | 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 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".