208 Chapter 8 steps toward urine-based diagnostics for ovarian cancer. Further research is needed to further explore and refine the use of urine biomarkers for ovarian cancer diagnostics. Part 2: Non-small cell lung cancer detection in urine In Part 2 of this thesis, the diagnostic potential of urine as a liquid biopsy for non-small cell lung cancer (NSCLC) detection was evaluated. In Chapter 6, the feasibility of primary and recurrent NSCLC detection in urine by DNA methylation testing was assessed. Urine was collected from patients with nonmetastatic NSCLC (n=46) and sex and age-matched controls (n=50) to assess the potential of urine for lung cancer detection. Three methylation markers (CDO1, SOX17, TAC1), previously described for NSCLC detection in plasma, sputum, and urine, were tested. Increased methylation levels were found for CDO1 and SOX17, with a combined AUC value of 0.71 after cross-validation. We collected a postoperative urine sample from a subset of patients (n=14) to explore the potential of postoperative monitoring and showed that in 10 patients with preoperatively elevated methylation levels, reduced methylation levels were found postoperatively. This study demonstrates that urine methylation tests provide an interesting means to support primary and recurrent lung cancer diagnoses. In Chapter 7, the dynamics of methylated urinary cell-free DNA (cfDNA) in NSCLC patients were evaluated to determine whether a preferred urine collection time and frequency exists. Six urine samples were prospectively collected from patients with advanced stage NSCLC (n=23) during the morning, afternoon, and evening of two subsequent days. No clear circadian pattern was found for urinary cfDNA concentrations or methylation levels across the sampling time points. While our data suggest that no preferred collection time exists, the frequency of sampling may increase the chance of detecting NSCLC in urine. Substantial variability between- and within-patients was observed and, therefore, serial sampling may increase urine test performance. The considerable biological variation of cfDNA found in this study underlines that single urine test measurements should be interpreted carefully. The outcomes of Part 2 demonstrate the technical feasibility of detecting NSCLC in the urine using DNA methylation markers. Further research, including larger patient cohorts and controls with benign pulmonary nodules, is needed to validate the clinical usefulness of this approach. The considerable variability between urine samples highlights the need for a more thorough understanding of cfDNA dynamics and enhancements in test development to ensure reliability. Upon further refinement, this test has the potential to serve as a valuable complementary diagnostic tool to low-dose CT screening to guide clinical decisions in patients with pulmonary nodules.
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