Novel urinary liquid biopsy biomarkers and their role in detecting genitourinary cancers

Liquid biopsy offers significant advantages over traditional tissue biopsy for cancer diagnosis and monitoring, including reduced invasiveness and better representation of tumor heterogeneity. In the context of GU cancers, such as bladder, renal, and prostate cancers, urine is a particularly valuable resource due to its production and storage near the tumor microenvironment. This review highlights the potential of urinary biomarkers in improving the detection, diagnosis, and monitoring of GU cancers.

Mutational and Fragmentation Analysis of ctDNA/cfDNA

Recent studies underscore the diagnostic potential of circulating tumor DNA (ctDNA) and cfDNA. ctDNA, released by dying cancer cells, can be detected in bodily fluids like urine. Ou et al. (2018) established a five-gene panel using cfDNA from urine supernatant for bladder cancer detection, achieving an AUROC of 0.94. Russo et al. (2019) employed digital droplet PCR to identify TERT promoter mutations in urinary cfDNA, with 92% sensitivity and 96% specificity. These findings suggest that ctDNA and cfDNA analyses can significantly enhance early cancer detection and monitoring.

DNA Methylation

Epigenetic alterations, particularly DNA methylation, are crucial in cancer progression. Studies have shown that hypermethylation of cfDNA can serve as a biomarker for GU cancers. Nuzzo et al. (2020) identified specific methylation patterns in plasma and urine cfDNA from renal cell carcinoma (RCC) patients, achieving an AUROC of 0.858. Similarly, Kubiliute et al. (2021) identified highly methylated genes in urinary DNA from RCC patients, validating their approach with a sensitivity of 69-78%. For bladder cancer, Feber et al. (2017) developed the UroMark assay, which achieved 96% sensitivity and 97% specificity using methylated DNA from urine sediment. These studies highlight the potential of DNA methylation as a non-invasive diagnostic tool.

Extracellular RNAs and Exosomes

Extracellular RNAs (exRNAs) and exosome cargos have emerged as promising biomarkers for GU cancers. exRNAs, including microRNAs (miRNAs), are stable in urine and reflect the tumor's genetic and epigenetic alterations. Exosomes, small vesicles secreted by cells, carry molecular information from their cell of origin. Studies have shown that exosome-derived biomarkers can differentiate between cancerous and non-cancerous conditions, providing a non-invasive method for cancer detection. For instance, exosomal miRNAs like miR-375 and miR-21 have been linked to prostate cancer, and their urinary levels correlate with disease presence and progression.

Challenges and Future Directions

Despite the promising potential of urinary biomarkers, several challenges remain. Standardizing urine collection and processing protocols is critical to ensure consistency and reliability of biomarker measurements. Moreover, large-scale validation studies are necessary to confirm the clinical utility of these biomarkers across diverse populations and settings. Future research should also explore the integration of multiple biomarker types, such as combining cfDNA, DNA methylation, and exRNA analyses, to enhance diagnostic accuracy and provide comprehensive insights into tumor biology.

Conclusions

The identification and validation of novel urinary biomarkers for GU cancers represent a significant advancement in non-invasive cancer diagnostics. These biomarkers offer the potential for routine screening, early detection, and monitoring of cancer progression, ultimately improving patient outcomes. Continued research and technological innovations will be key to overcoming current challenges and fully realizing the clinical benefits of urinary liquid biopsy in the management of GU cancers.

Full text

https://www.xiahepublishing.com/2771-165X/JCTP-2022-00030

The study was recently published in the Journal of Clinical and Translational Pathology.

Journal of Clinical and Translational Pathology (JCTP) is the official scientific journal of the Chinese American Pathologists Association (CAPA). It publishes high quality peer-reviewed original research, reviews, perspectives, commentaries, and letters that are pertinent to clinical and translational pathology, including but not limited to anatomic pathology and clinical pathology. Basic scientific research on pathogenesis of diseases as well as application of pathology-related diagnostic techniques or methodologies also fit the scope of the JCTP.

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