title: Bladder cancer biomarker discovery using global metabolomic profiling of urine.
abstract: Bladder cancer (BCa) is a common malignancy worldwide and has a high probability of recurrence after initial diagnosis and treatment. As a result, recurrent surveillance, primarily involving repeated cystoscopies, is a critical component of post diagnosis patient management. Since cystoscopy is invasive, expensive and a possible deterrent to patient compliance with regular follow-up screening, new non-invasive technologies to aid in the detection of recurrent and/or primary bladder cancer are strongly needed. In this study, mass spectrometry based metabolomics was employed to identify biochemical signatures in human urine that differentiate bladder cancer from non-cancer controls. Over 1000 distinct compounds were measured including 587 named compounds of known chemical identity. Initial biomarker identification was conducted using a 332 subject sample set of retrospective urine samples (cohort 1), which included 66 BCa positive samples. A set of 25 candidate biomarkers was selected based on statistical significance, fold difference and metabolic pathway coverage. The 25 candidate biomarkers were tested against an independent urine sample set (cohort 2) using random forest analysis, with palmitoyl sphingomyelin, lactate, adenosine and succinate providing the strongest predictive power for differentiating cohort 2 cancer from non-cancer urines. Cohort 2 metabolite profiling revealed additional metabolites, including arachidonate, that were higher in cohort 2 cancer vs. non-cancer controls, but were below quantitation limits in the cohort 1 profiling. Metabolites related to lipid metabolism may be especially interesting biomarkers. The results suggest that urine metabolites may provide a much needed non-invasive adjunct diagnostic to cystoscopy for detection of bladder cancer and recurrent disease management.
authors.affiliation: Clinical Research and Development, Metabolon Inc., Durham, North Carolina, United States of America.
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Wittmann
authors.affiliation: Clinical Research and Development, Metabolon Inc., Durham, North Carolina, United States of America.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Stirdivant
authors.affiliation: Clinical Research and Development, Metabolon Inc., Durham, North Carolina, United States of America.
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Mitchell
authors.affiliation: Clinical Research and Development, Metabolon Inc., Durham, North Carolina, United States of America.
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Wulff
authors.affiliation: Clinical Research and Development, Metabolon Inc., Durham, North Carolina, United States of America.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: McDunn
authors.affiliation: Clinical Research and Development, Metabolon Inc., Durham, North Carolina, United States of America.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Aphrihl
authors.initials: A
authors.lastname: Dennis-Barrie
authors.affiliation: Clinical Research and Development, Metabolon Inc., Durham, North Carolina, United States of America.
authors.forename: Bruce P
authors.initials: BP
authors.lastname: Neri
authors.affiliation: Clinical Research and Development, Metabolon Inc., Durham, North Carolina, United States of America.
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.affiliation: Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Yair
authors.initials: Y
authors.lastname: Lotan
authors.affiliation: Clinical Research and Development, Metabolon Inc., Durham, North Carolina, United States of America.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Wolfert
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism* / Q000652:urine*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D011379:Prognosis; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000652:urine*
chemical_list: D014408:Biomarkers, Tumor