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Association Of Plasma And Urinary Mutant DNA With Clinical Outcomes In Muscle Invasive Bladder Cancer

Published version
Peer-reviewed

Type

Article

Change log

Authors

Patel, KM 
van der Vos, KE 
Smith, CG 
Tsui, D 

Abstract

Muscle Invasive Bladder Cancer (MIBC) has a poor prognosis. Whilst patients can achieve a 6% improvement in overall survival with Neo-Adjuvant Chemotherapy (NAC), many do not respond. Body fluid mutant DNA (mutDNA) may allow non-invasive identification of treatment failure. We collected 248 liquid biopsy samples including plasma, cell pellet (UCP) and supernatant (USN) from spun urine, from 17 patients undergoing NAC. We assessed single nucleotide variants and copy number alterations in mutDNA using Tagged-Amplicon- and shallow Whole Genome- Sequencing. MutDNA was detected in 35.3%, 47.1% and 52.9% of pre-NAC plasma, UCP and USN samples respectively, and urine samples contained higher levels of mutDNA (p = <0.001). Longitudinal mutDNA demonstrated tumour evolution under the selective pressure of NAC e.g. in one case, urine analysis tracked two distinct clones with contrasting treatment sensitivity. Of note, persistence of mutDNA detection during NAC predicted disease recurrence (p = 0.003), emphasising its potential as an early biomarker for chemotherapy response.

Description

Keywords

Aged, DNA, Neoplasm, Female, Follow-Up Studies, Genome, Human, Humans, Male, Middle Aged, Mutation, Neoadjuvant Therapy, Neoplasm Recurrence, Local, Treatment Outcome, Urinary Bladder Neoplasms

Journal Title

Scientific Reports

Conference Name

Journal ISSN

2045-2322
2045-2322

Volume Title

7

Publisher

Nature Publishing Group
Sponsorship
European Research Council (337905)
Cancer Research UK (C14303/A17197)
Cancer Research UK (C48525/A18345)
Cancer Research UK (20240)
We would like to thank the CRUK-CI core facilities in particular; the bio-repository, genomic and bioinformatic cores. We are grateful for support from Cancer Research UK, the University of Cambridge and the Netherlands Cancer Institute. CGS and CEM were supported by European Research Council [337905]. KP was supported by the Cambridge Cancer Centre [A18345], the Royal College of Surgeons of England [KEVAL PATEL] and the Addenbrookes Charitable Trust [28/13A 9935]. MSH was supported by a grant from the Netherlands Organization for Scientific Research (NWO, Veni program).