Integrated Plasma and Urinary Cell-free DNA Profiling Enables Noninvasive Molecular Detection from Ta to T4 Bladder Cancer
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Background and Objective
Due to the heterogeneity of bladder cancer, minimally invasive molecular profiling may improve tumor characterization at the time of diagnosis. We evaluated whether integrated genomic and fragmentomic profiling of plasma and urinary circulating tumor DNA (ctDNA) detects BC-derived signals for diagnosis and disease stratification across all tumor stages.
Methods
In this real-world cohort, 202 plasma and urine samples were obtained from 33 patients with non-muscle-invasive BC (NMIBC), mostly Ta tumors, and 15 patients with muscle-invasive BC (MIBC), as well as from 58 cancer-free controls. Low-coverage whole-genome sequencing was performed to assess ctDNA fragmentation, chromosomal instability and copy number variations. Matched tumor tissue was analyzed to evaluate concordance between liquid biopsy and tissue-derived molecular alterations.
Key Findings and Limitations
Complementary genomic and fragmentomic profiling of cfDNA achieved detection rates of 75.8% in NMIBC patients and 91.7% in MIBC patients with paired plasma and urine. Distinct differences were observed between MIBC, NMIBC and cancer-free controls, consistent with increasing ctDNA signals during disease progression. Tumor tissue analysis confirmed BC-associated molecular alterations. Limitations include the single-center design and limited sample size.
Conclusions and Clinical Implications
Multimodal profiling of plasma and urinary cfDNA enabled the detection of tumor-derived molecular signals for all bladder cancer stages, including early-stage disease. By integrating genomic and fragmentomic features, this minimally invasive approach provides molecular tumor characterization at the time of diagnosis and may support future risk-adapted diagnostic, therapeutic and surveillance strategies.
Advancing Practice
What does this study add?
Our study demonstrates the potential of integrating multiple biomarkers from two liquid biopsy sources for minimally-invasive bladder cancer (BC) detection. This strategy enhances diagnostic sensitivity and addresses the limitations of single-analyte approaches, making it particularly relevant for future diagnostic and risk stratification in early stages, where circulating tumor-derived DNA levels are low. Multimodal liquid biopsy could serve as a valuable non-invasive method to guide clinical decisions, including additional diagnostics such as imaging and cystoscopy, as well as subsequent therapy management such as adjuvant therapy and follow-up.
Patient Summary
In this study, we explored a liquid biopsy approach using blood and urine to detect bladder cancer and assess its aggressiveness. We found that combining different genomic and fragmentomic markers improved the identification of tumor signals, even in early-stage cases. In the future, such approaches could help doctors to better assess bladder cancer risk and to personalize treatment decisions.
