Project description:Platinum-based treatment (e.g., cisplatin, carboplatin) is generally the first-line chemotherapy for muscle-invasive bladder cancer (MIBC) and mediates regression in approximately 50% of the patients. The goal of this study was to improve the response rate to platinum-based treatment by developing a genomics-based method capable of classifying MIBC patients as being either likely to respond to therapy versus not likely to respond. Aberrations in TP53 and its downstream effectors play a key role in promoting bladder cancer progression, however, TP53 mutation status is neither an independent indicator of treatment response nor survival in MIBC. The hypothesis of this study was that evaluating overall TP53 function would be informative in predicting responsiveness to therapy. Towards this goal, we developed a custom-designed “TP53 functional miRGE assay”, which assesses TP53 function by simultaneously measuring the expression of 105 TP53-responsive mRNAs and miRNAs using NanoString nCounter technology. Expression profiling was performed on a panel of 34 therapy-naïve MIBC specimens with known outcomes of either being responsive or resistant. Clustering analysis identified a 7-gene subset of TP53 network genes (BAK1, BAX, BBC3, CDKN1A, MDM2, PMAIP1, TP53), which identified patients who did not respond to chemotherapy with 92.3% accuracy. Furthermore, higher TP53 function was associated more with resistant MIBCs in that these exhibited higher relative expression of TP53 target genes. Our results demonstrate a 7-gene TP53 functional assay using NanoString technology has the potential to predict patient response to platinum-based chemotherapy, and that validation of this method using a larger patient sample set is warranted.
Project description:Improved risk stratification and predictive biomarkers of treatment response are needed for non–muscle-invasive bladder cancer (NMIBC). Here we assessed the clinical utility of targeted RNA and DNA molecular profiling in NMIBC. We performed RNA-based profiling by NanoString nCounter on non–muscle-invasive bladder cancer (NMIBC) clinical specimens and found that a novel expression signature of an inflamed tumor microenvironment (TME), but not molecular subtyping, was associated with improved recurrence-free survival after bacillus Calmette-Guérin (BCG) immunotherapy. We further demonstrated that immune checkpoint gene expression was not associated with higher recurrence rates after BCG.
Project description:Purpose: Selecting muscle-invasive bladder cancer patients for adjuvant therapy is currently based on clinical variables with limited power. We hypothesized that genomic-based signatures can outperform clinical models to identify patients at higher risk. Method:Transcriptome-wide expression profiles were generated using 1.4 million feature-arrays on archival tumors from 225 patients who underwent radical cystectomy and had muscle-invasive and/or node-positive bladder cancer. A 15-feature GC was developed on the discovery set with area under curve (AUC) of 0.77 in the validation set. A cohort comprised of 225 patients with organ-confined, muscle-invasive (pT2N0M0),extravesical (pT3-4aN0M0), and node-positive (pTanyN1-3M0) UCB who underwent radicalcystectomy at the University of Southern California between 1998 and 2004 was used. Each patient had aminimum two-year follow-up post-cystectomy unless they recurred prior to that date. Patients receiving neoadjuvant chemotherapy, and those with clinical evidence of lymphadenopathy or distant metastasis at diagnosis were excluded.
Project description:Four different molecular classifications of muscle-invasive bladder cancer (MIBC) based on gene expression have been proposed. With the ultimate goal of utilizing these molecular subtypes for personalized treatment, we investigated their significance in the context of neoadjuvant cisplatin-based chemotherapy (NAC).
Project description:This RNA-sequencing cohort includes 52 Non-muscle Invasive Bladder cancer (NMIBC) samples and 6 Muscle Invasive Bladder cancer (MIBC) samples.
Project description:At diagnosis approximately 75% of bladder urothelial carcinomas are non muscle invasive bladder cancers (Ta, T1 and Tis), 20% are muscle invasive bladder cancer (T2-T4) and 5% are already metastatic. Non muscle invasive bladder cancers are characterized by tumor recurrence in 60% to 85% of cases and, therefore, long-term followup is needed. The current standard methods to detect and monitor bladder cancer are cystoscopy and cytology. Cystoscopy is an invasive method and cytology is hampered by low sensitivity, especially for low grade tumors. So there is need to develop reliable and noninvasive methods to detect and predict bladder cancer biological behavior. So we have performed high density oligonucleotide microarray for discovery of new molecular markers to diagnose and predict the outcome of bladder cancer. Under an ethical guideline of Chhatrapati Shahuji Maharaj Medical University, India histologically confirmed seven bladder cancer patients were recruited from Department of Urology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, India. Total RNA was extracted from tumor biopsies and hybridized on affymetrix Human Gene ST 1.1 array to determine differentially expressed genes in urinary bladder cancer with muscle invasion in comparison of normal human urinary bladder.
Project description:Identifying patients that benefit from cisplatin-based adjuvant chemotherapy is a major issue in the management of muscle-invasive bladder cancer (MIBC). The purpose of this study is to correlate “luminal” and “basal” type protein expression with histological subtypes, to investigate the prognostic impact on survival after adjuvant chemotherapy and to define molecular subtypes of “double negative” patients (i.e. without expression of CK5/6 or GATA3).
