Age-related bladder dysfunction and mitochondrial biology
This project aims to establish the suitability of measuring mitochondrial DNA (mtDNA) by sequencing Non-muscle Invasive Bladder Cancer patients’ urine.
Bladder cancer is the most common urinary tract cancer with over 10,000 new UK diagnoses annually and illustrates well the association between ageing and cancer. The current diagnostic test requires cystoscopy, a procedure to visualise inside the bladder, which is invasive, uncomfortable and time consuming. Bladder Cancer requires lifelong monitoring for many patients thus being one of the most expensive cancers to manage on the NHS.
The major clinical problem is the 40% risk of recurrence within 3 years. Associated with recurrence is the risk of stage progression to muscle invasive cancer carrying a high mortality risk. Half of all recurrence is caused by incomplete tumour removal.
Currently, there are no bladder urinary biomarkers in routine clinical use to detect bladder tumour cells and urine provides a non-invasive liquid biopsy of bladder tumour mtDNA. A urinary molecular marker to detect either macroscopic residual disease or early growth from presentation of microscopic residual disease would transform clinical practice by confirming Bladder Cancer recurrence and relieving the reliance on surveillance cystoscopy.
We are establishing the suitability of measuring mitochondrial DNA (mtDNA) by sequencing Non-muscle Invasive Bladder Cancer patients’ urine. This involves urine and blood based mitochondrial DNA targeted deep whole exome sequencing from patients undergoing Robotic Cystectomy.
Testing the hypothesis: mtDNA mutations in urine act as a lineage tracing mark for incomplete tumour resection we have identified tumour specific novel mtDNA variants that are absent from the patients’ normal urothelium.
Bladder tumours possess a unique mtDNA genotype, or barcode, that can be readily detected in patients’ urine. Taking advantage of this liquid biopsy of bladder tumour mtDNA offers an exciting novel non-invasive paradigm to trace bladder cancer recurrence.
- Establish suitability of measuring free mtDNA sequencing in urine.
- mtDNA mutation characterisation in human urothelial cells from urine, bladder tissue (benign/malignant) and blood from patients undergoing Robotic Cystectomy.
- Correlate mtDNA mutation profile molecular readouts with clinical measures and clinicopathological patient notes to appreciate the translational value.
- Lineage trace mtDNA mutations in PHOTO-T cohort to determine BC recurrence. This will test the hypothesis that mtDNA mutations in urine act as a lineage tracing mark for incomplete tumour resection, using the PHOTO clinical cohort, a unique collection with serial measures.