TP63 isoform expression is linked with distinct clinical outcomes in cancer

Abstract

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 0.80À0.99, 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 1.64À3.37, 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.

The foggy world(s) of p63 isoform regulation in normal cells and cancer

“…Clinically, p63 has value in identifying malignancy and for tumour classification, and isoform‐specific ΔNp63 antibodies are superior to assessing total p63 in many situations (reviewed in ref 249). In addition, although not well studied in clinical material, TAp63 provides prognostic information [15,18,249–251] and requires more study in lymphomas and lymphocytes (including tumour‐infiltrating lymphocytes) to understand its prognostic impact and opportunities for therapy. Advances in understanding p63 isoforms and their regulation will inevitably lead to new diagnostic, prognostic and therapeutic opportunities for cancer and other pathological conditions.…”

Research and Clinical Significance of the Differentially Expressed Genes TP63 and LMO4 in Human Immunodeficiency Virus-related Penile Squamous Cell Carcinoma

“…TP63 is considered a transcriptional regulator of the basal gene program and is upregulated in basal subtypes of bladder, breast and ovarian cancers [12]. The enrichment of immune pathways in TAp63-expressing tumors suggests a link between TAp63 and tumor immune in ltrates [18]. An aggressive basal subtype of bladder cancer can be identi ed by the activation of TP63-driven genetic programs, which share the same molecular characteristics as squamous tumors occurring in other organs [19].…”

Research and Clinical Significance of the Differentially Expressed Genes TP63 and LMO4 in Human Immunodeficiency Virus-Related Penile Squamous Cell Carcinoma

“…TP63 is considered a transcriptional regulator of the basal gene program and is upregulated in basal subtypes of bladder, breast, and ovarian cancers. The enrichment of immune pathways in TAp63expressing tumors suggests a link between TAp63 and tumor immune infiltrates (Bankhead et al, 2020).…”