Abstract
Bladder cancer is diagnosed by cystoscopy, a costly and invasive procedure that is associated with patient discomfort. Analysis of tumor-specific markers in DNA from sediments of voided urine has the potential for non-invasive detection of bladder cancer; however, the sensitivity is limited by low fractions and small numbers of tumor cells exfoliated into the urine from low-grade tumors. The purpose of this study was to improve the sensitivity for non-invasive detection of bladder cancer by size-based capture and enrichment of tumor cells in urine. In a split-sample set-up, urine from a consecutive series of patients with primary or recurrent bladder tumors (N = 189) was processed by microfiltration using a membrane filter with a defined pore-size, and sedimentation by centrifugation, respectively. DNA from the samples was analyzed for seven bladder tumor-associated methylation markers using MethyLight and pyrosequencing assays. The fraction of tumor-derived DNA was higher in the filter samples than in the corresponding sediments for all markers (p<0.000001). Across all tumor stages, the number of cases positive for one or more markers was 87% in filter samples compared to 80% in the corresponding sediments. The largest increase in sensitivity was achieved in low-grade Ta tumors, with 82 out of 98 cases positive in the filter samples (84%) versus 74 out of 98 in the sediments (75%). Our results show that pre-analytic processing of voided urine by size-based filtration can increase the sensitivity for DNA-based detection of bladder cancer.
Highlights
Bladder cancer is the seventh most common cancer worldwide and accounts for more than 150,000 deaths each year [1]
Non-invasive assays that can accurately and reliably detect bladder cancer will have a substantial impact on patients and the healthcare system by reducing the need for frequent, costly and uncomfortable cystoscopy
Significant progress has been made in identifying urine-based biomarkers that can outperform urine cytology, and some of these markers have been developed into commercial tests
Summary
Bladder cancer is the seventh most common cancer worldwide and accounts for more than 150,000 deaths each year [1]. Typical symptoms of bladder cancer are microscopic and macroscopic hematuria, painful urination and polyuria. None of these symptoms is specific for the disease and can be caused by a range of other conditions including cystitis, kidney stones and prostate disease. Most patients are diagnosed with non-invasive bladder cancer (stage Ta), which has a five-year survival rate of 90%. The recurrence rate is high (50–70%) and 10–25% progress to invasive bladder cancer, warranting long-term followup by cystoscopy in patients with non-invasive tumors [2,3,4]. Cystoscopy is an invasive method that is uncomfortable for patients and requires great technical and financial resources It is, important to develop non-invasive methods that are simple and cost-effective for diagnosis and follow-up of bladder cancer
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