Mitochondrial DNA as a biomarker for Bladder Cancer

Abstract

Introduction Although we take bladder function for granted, across the world ageing brings symptomatic lower urinary tract dysfunction to many individuals and risk of malignant transformation. Bladder cancer is the most prevalent urinary tract cancer and one of the most expensive cancers to manage on the NHS. The current diagnostic test, cystoscopy is invasive requiring lifelong patient monitoring. The major clinical problem is a 40% risk of recurrence within 3 years. Associated with recurrence is the risk of stage progression to muscle-invasive, carrying a high mortality risk. Herein, lies the unique translational opportunity of mitochondrial DNA (mtDNA). During ageing, mtDNA accumulates transformations that can lead to disease. Clonally expanded mtDNA variations have been observed in many tumours and I investigated whether clonally expanded mtDNA transformations are present in bladder tumours. Importantly, as tumour cells are readily shed into the urine, I explored the detection of clonally expanded mtDNA alterations in urine. Methods Following Radical Cystectomy, bladder tumour tissue, normal bladder tissue, matched urine, and blood were collected. DNA was extracted and PCR was performed to amplify mtDNA and mtDNA sequencing to detect mtDNA genotypes specific to the tumour. Bladder tissue sections were cut, stained with Haematoxylin and Eosin, and tumour content was determined by Pathologists. Results Tumour-specific mtDNA variants were detected in all patients with confirmed tumour tissue and were undetected or found at markedly lower or higher levels in the patient’s normal bladder lining. These tumour-specific mtDNA genotypes were also identified within the patients’ urine and formalin-fixed paraffin-embedded (FFPE) bladder tumour samples. Conclusion Bladder tumours possess a unique mtDNA genotype or barcode, that can be readily detected in patients’ urine and FFPE bladder tumour material. Taking advantage of urine, a liquid biopsy of bladder tumour mtDNA offers a non-invasive paradigm to trace Bladder Cancer recurrence.