Rosser, Charles J

Purpose: Bladder cancer (BCa) is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. In previous studies, we and others have described the functional influence of plasminogen activator inhibitor-1 (PAI1) in bladder cancer development. While polymorphisms in PAI1 have been associated with increased risk and worsened prognosis in some cancers, the mutational status of PAI1 in human bladder tumors has not been well defined. Methods: In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects. Results: Sequencing analyses identified two clinically relevant 3′ untranslated region (UTR) single nucleotide polymorphisms (SNPs) in PAI1 (rs7242; rs1050813). Somatic SNP rs7242 was present in human BCa cohorts (overall incidence of 72%; 62% in Caucasians and 72% in Asians). In contrast, the overall incidence of germline SNP rs1050813 was 18% (39% in Caucasians and 6% in Asians). Furthermore, Caucasian patients with at least one of the described SNPs had worse recurrence-free survival and overall survival (p = 0.03 and p = 0.03, respectively). In vitro functional studies demonstrated that SNP rs7242 increased the anti-apoptotic effect of PAI1, and SNP rs1050813 was related to a loss of contact inhibition associated with cellular proliferation when compared to wild type. Conclusion: Further investigation of the prevalence and potential downstream influence of these SNPs in bladder cancer is warranted.

Bladder cancer is a biologically heterogeneous disease with variable clinical presentations, outcomes and responses to therapy. Thus, the clinical utility of single biomarkers for the detection and prediction of biological behavior of bladder cancer is limited. We have previously identified and validated a bladder cancer diagnostic signature composed of 10 biomarkers, which has been incorporated into a multiplex immunoassay bladder cancer test, Oncuria™. In this study, we evaluate whether these 10 biomarkers can assist in the prediction of bladder cancer clinical outcomes. Tumor gene expression and patient survival data from bladder cancer cases from The Cancer Genome Atlas (TCGA) were analyzed. Alignment between the mRNA expression of 10 biomarkers and the TCGA 2017 subtype classification was assessed. Kaplan–Meier analysis of multiple gene expression datasets indicated that high expression of the combined 10 biomarkers correlated with a significant reduction in overall survival. The analysis of three independent, publicly available gene expression datasets confirmed that multiplex prognostic models outperformed single biomarkers. In total, 8 of the 10 biomarkers from the Oncuria™ test were significantly associated with either luminal or basal molecular subtypes, and thus, the test has the potential to assist in the prediction of clinical outcome.

Background: The Oncuria™ urine test for the detection of bladder cancer measures a multiplex protein signature. In this study, we investigated the influence of urinary cellularity, protein, and hematuria on the performance of the Oncuria™ test in an ex vivo experimental model. Materials and Methods: Pooled urine from healthy subjects was spiked with cultured benign (UROtsa) or malignant cells (T24), cellular proteins, or whole blood. The resulting samples were analyzed using the Oncuria™ test following the manufacturer’s instructions. Results: Urine samples obtained from healthy subjects were negative for bladder cancer by Oncuria™ test criteria. The majority of the manipulated conditions did not result in a false-positive test. The addition of whole blood (high concentration) did result in a false-positive result, but this was abrogated by sample centrifugation prior to analysis. The addition of cellular proteins (high concentration) resulted in a positive Oncuria™ test, and this was unaffected by pre-analysis sample centrifugation. Conclusions: The Oncuria™ multiplex test performed well in the ex vivo experimental model and shows promise for clinical application. The identification of patients who require additional clinical evaluation could reduce the need to subject patients who do not have bladder cancer to frequent, uncomfortable and expensive cystoscopic examinations, thus benefiting both patients and the healthcare system.