TP63 isoform expression is linked with distinct clinical outcomes in cancer
| Autor: | Phillip L. Palmbos, Philip S. Boonstra, Yin Wang, Thomas McMaster, Armand Bankhead |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Gene isoform Oncology medicine.medical_specialty Research paper Bladder cancer patient lcsh:Medicine Disease General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Internal medicine Cell Line Tumor TP63 medicine Humans Protein Isoforms Gene Proportional Hazards Models Cancer lcsh:R5-920 Bladder cancer business.industry Tumor Suppressor Proteins lcsh:R General Medicine Biomarker medicine.disease Survival Analysis Bladder Cancer 3. Good health Gene Expression Regulation Neoplastic 030104 developmental biology Treatment Outcome Urinary Bladder Neoplasms 030220 oncology & carcinogenesis Cohort lcsh:Medicine (General) business Isoforms Human cancer Signal Transduction Transcription Factors |
| Zdroj: | EBioMedicine EBioMedicine, Vol 51, Iss, Pp-(2020) |
| ISSN: | 2352-3964 |
| Popis: | Background: Half of muscle-invasive bladder cancer patients will relapse with metastatic disease and molecular tests to predict relapse are needed. TP63 has been proposed as a prognostic biomarker in bladder cancer, but reports associating it with clinical outcomes are conflicting. Since TP63 is expressed as multiple isoforms, we hypothesized that these conflicting associations with clinical outcome may be explained by distinct opposing effects of differential TP63 isoform expression. Methods: Using RNA-Seq data from The Cancer Genome Atlas (TCGA), TP63 isoform-level expression was quantified and associated with clinical covariates (e.g. survival, stage) across 8,519 patients from 29 diseases. A comprehensive catalog of TP63 isoforms was assembled using gene annotation databases and de novo discovery in bladder cancer patients. Quantifications and un-annotated TP63 isoforms were validated using quantitative RT-PCR and a separate bladder cancer cohort. Findings: DNp63 isoform expression was associated with improved bladder cancer patient survival in patients with a luminal subtype (HR = 0.89, CI 0.80–0.99, Cox p = 0.034). Conversely, TAp63 isoform expression was associated with reduced bladder cancer patient survival in patients with a basal subtype (HR = 2.35, CI 1.64–3.37, Cox p < 0.0001). These associations were observed in multiple TCGA disease cohorts and correlated with epidermal differentiation (DNp63) and immune-related (TAp63) gene signatures. Interpretation: These results comprehensively define TP63 isoform expression in human cancer and suggest that TP63 isoforms are involved in distinct transcriptional programs with opposing effects on clinical outcome. Keywords: TP63, Isoforms, Cancer, Bladder Cancer, Biomarker |
| Databáze: | OpenAIRE |
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