Metabolomic Profiling Reveals Potential Markers and Bioprocesses Altered in Bladder Cancer Progression

• Type of Material: Article
• Authors: Nagireddy Putluri, Baylor College of Medicine; Ali Shojaie, University of Michigan; Vihas T Vasu, Georgia Health Science University; Shaiju K. Vareed, Baylor College of Medicine; Srilatha Nalluri, Georgia Health Science University; Vasanta Putluri, Baylor College of Medicine; Gagan Singh Thangjam, Georgia Health Science University; Katrin Panzitt, Baylor College of Medicine; Christopher T. Tallman, University of Michigan; Charles Butler, Emory University; Theodore R. Sana, Agilent Technologies; Steven M. Fischer, Agilent Technologies; Gabriel Sica, Emory University; Daniel J Brat, Emory University; Huidong Shi, Methodist Hospital; Ganesh S Palapattu, Methodist Hospital; Yair Lotan, University of Texas Southwestern Medical Dallas; Alon Z. Weizer, University of Michigan; Martha K. Terris, Georgia Health Science University; Shahrokh F. Shariat, Cornell University; George Michailidis, University of Michigan; Arun Sreekumar, Baylor College of Medicine
• Language: English
• Date: 2011-12-15
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2011 AACR.
• Final Published Version (URL): http://dx.doi.org/10.1158/0008-5472.CAN-11-1154
• Title of Journal or Parent Work: Cancer Research
• ISSN: 0008-5472
• Volume: 71
• Issue: 24
• Start Page: 7376
• End Page: 7386
• Grant/Funding Information: This work is supported in part by the National Cancer Institute grant RO1CA13345 (AS); RO3CA139489-01 (AS); and RCA145444A (AS and GM); and funds to AS from the Alkek Center for Molecular Discovery; Baylor College of Medicine and Georgia Cancer Coalition.
• Keywords: Life Sciences & Biomedicine; POLYMORPHISMS; ASSOCIATION; Oncology; GSTM1; PHENOTYPE; GSTP1; CYP1A2; RISK; WORKERS; PROSTATE-CANCER; Science & Technology; GSTT1
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery; Health Sciences, Pathology

Abstract

Although alterations in xenobiotic metabolism are considered causal in the development of bladder cancer, the precise mechanisms involved are poorly understood. In this study, we used high-throughput mass spectrometry to measure over 2,000 compounds in 58 clinical specimens, identifying 35 metabolites which exhibited significant changes in bladder cancer. This metabolic signature distinguished both normal and benign bladder from bladder cancer. Exploratory analyses of this metabolomic signature in urine showed promise in distinguishing bladder cancer from controls and also nonmuscle from muscle-invasive bladder cancer. Subsequent enrichment-based bioprocess mapping revealed alterations in phase I/II metabolism and suggested a possible role for DNA methylation in perturbing xenobiotic metabolism in bladder cancer. In particular, we validated tumor-associated hypermethylation in the cytochrome P450 1A1 (CYP1A1) and cytochrome P450 1B1 (CYP1B1) promoters of bladder cancer tissues by bisulfite sequence analysis and methylation-specific PCR and also by in vitro treatment of T-24 bladder cancer cell line with the DNA demethylating agent 5-aza-2′-deoxycytidine. Furthermore, we showed that expression of CYP1A1 and CYP1B1 was reduced significantly in an independent cohort of bladder cancer specimens compared with matched benign adjacent tissues. In summary, our findings identified candidate diagnostic and prognostic markers and highlighted mechanisms associated with the silencing of xenobiotic metabolism. The metabolomic signature we describe offers potential as a urinary biomarker for early detection and staging of bladder cancer, highlighting the utility of evaluating metabolomic profiles of cancer to gain insights into bioprocesses perturbed during tumor development and progression.