title: Genomic Alterations in Liquid Biopsies from Patients with Bladder Cancer.
abstract: At least half of the patients diagnosed with non-muscle-invasive bladder cancer (NMIBC) experience recurrence and approximately 15% will develop progression to muscle invasive or metastatic disease. Biomarkers for disease surveillance are urgently needed.
  
  
  
  Development of assays for surveillance using genomic variants in cell-free tumour DNA from plasma and urine.
  
  
  
  Retrospective pilot study of 377 samples from 12 patients with recurrent or progressive/metastatic disease. Three next-generation sequencing methods were applied and somatic variants in DNA from tumour, plasma, and urine were subsequently monitored by personalised assays using droplet digital polymerase chain reaction (ddPCR). Samples were collected from 1994 to 2015, with up to 20 yr of follow-up.
  
  
  
  Progression to muscle-invasive or metastatic bladder cancer; t test for ddPCR data.
  
  
  
  We developed from one to six personalised assays per patient. Patients with progressive disease showed significantly higher levels of tumour DNA in plasma and urine before disease progression, compared with patients with recurrent disease (p=0.032 and 1.3×10(-6), respectively). Interestingly, tumour DNA was detected in plasma and urine in patients with noninvasive disease, being no longer detectable in disease-free patients. A significant level of heterogeneity was observed for each patient; this could be due to tumour heterogeneity or assay performance.
  
  
  
  Cell-free tumour DNA can be detected in plasma and urine, even in patients with noninvasive disease, with high levels of tumour DNA detectable before progression, especially in urine samples. Personalised assays of genomic variants may be useful for disease monitoring.
  
  
  
  Tumour DNA can be detected in blood and urine in early and advanced stages of bladder cancer. Measurement of these highly tumour-specific biomarkers may represent a novel diagnostic tool to indicate the presence of residual disease or to discover aggressive forms of bladder cancer early in the disease course.
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark. Electronic address: kbdr@clin.au.dk.
authors.forename: Karin
authors.initials: K
authors.lastname: Birkenkamp-Demtröder
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark.
authors.forename: Iver
authors.initials: I
authors.lastname: Nordentoft
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark.
authors.forename: Emil
authors.initials: E
authors.lastname: Christensen
authors.affiliation: Department of Pathology, Aarhus University Hospital, Aarhus C, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Høyer
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Reinert
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark.
authors.forename: Søren
authors.initials: S
authors.lastname: Vang
authors.affiliation: Department of Urology, Aarhus University Hospital, Aarhus N, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Borre
authors.affiliation: Department of Oncology, Aarhus University Hospital, Aarhus C, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Agerbæk
authors.affiliation: Department of Urology, Aarhus University Hospital, Aarhus N, Denmark.
authors.forename: Jørgen Bjerggaard
authors.initials: JB
authors.lastname: Jensen
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark.
authors.forename: Torben F
authors.initials: TF
authors.lastname: Ørntoft
authors.affiliation: Department of Molecular Medicine, Aarhus University Hospital, Aarhus N, Denmark. Electronic address: lars@clin.au.dk.
authors.forename: Lars
authors.initials: L
authors.lastname: Dyrskjøt
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000652:urine; D004273:DNA, Neoplasm / Q000097:blood* / Q000652:urine*; D018450:Disease Progression; D005260:Female; D014644:Genetic Variation; D006801:Humans; D000073890:Liquid Biopsy; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology; D010865:Pilot Projects; D011159:Population Surveillance / Q000379:methods*; D012189:Retrospective Studies; D001743:Urinary Bladder / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm
keywords: Biomarker; Cell-free DNA; Circulating DNA; Droplet digital PCR; Genomic variant; NMIBC; Next-generation sequencing; Personalised analysis; Plasma; Urine