DNA Methylation Markers for early detection and monitoring the trajectory of tumor burden in Bladder Cancer - Summary Bladder cancer is one of the most common malignancies in the U.S. Non-muscle invasive bladder cancer (NMIBC) accounts for 80% of all incident cases with a high recurrence rate (up to 70%), for which the initial treatment is transurethral resection of bladder tumor (TURBT). Approximately 20% of patients initially present with muscle invasive bladder cancer (MIBC). For these patients, the gold standard treatment is neoadjuvant chemotherapy (NAC) followed by radical cystectomy, but despite aggressive surgical management, the overall 5-year survival rate in these patients is 50%. Currently there are no non-invasive methods to monitor recurrence and/or drug response during NAC. Thus, there is a critical unmet need for reliable markers that can detect recurrence of NMIBC at an earlier stage and monitor tumor response during treatment of MIBC. Aberrant DNA methylation is one of most common epigenetic changes during tumorigenesis. DNA methylation (DNAm) alterations are chemically stable and can be experimentally quantified, which makes them promising tumor markers for bladder cancer detection and monitoring. Studies, including those from our group, have shown that bladder cancer specific DNAm changes can be detected in urine sediments and can be used as diagnostic or monitoring markers. DNAm changes in urine sediments mirror those found in primary tumor tissues and serve as a non-invasive means to identify cancer-specific alterations. We can detect specific DNAm markers for each stage of disease, not only through direct tumor biopsies, but also non-invasively through analysis of patient urine sediments. When applying DNAm to monitor treatment response, the research efforts thus far have underutilized the strength of DNAm as a continuous, dynamic, longitudinal biomarker, and have treated DNAm as a fixed status (cross-sectional measurement) to predict either binary outcome status or survival status. Without seeing the full trajectory of DNAm data, it will be difficult to reach the ideal predictive performance for treatment response. Thus, a personalized medicine approach for monitoring recurrence of NMIBC and treatment of MIBC patients is urgently needed with a dynamic quantitative monitoring of tumor burden. The final goal of this study is to analyze the pattern of longitudinal trajectory of tumor burden quantified by DNAm for the prediction of treatment outcome of both NMIBC and MIBC. With the support evidence from our pilot data, we hypothesize that bladder cancer DNA methylation marker panels can be used to: 1) check residual tumor cells after transurethral resection of bladder tumor (TURBT) and 2) monitor recurrence of tumors after TURBT in patient urine sediments as active surveillance for NMIBC patients (Aim 1); 3) monitor the trajectory of tumor cells in urine sediments for the association with NAC treatment response in MIBC patients (Aim 2), thus indicating treatment response. We aim to collect 60 patients’ urine sediments during/after TURBT and 70 patients for NAC treatment.
