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770.Full-Text.Pdf Published OnlineFirst January 14, 2019; DOI: 10.1158/1055-9965.EPI-18-0936 Research Article Cancer Epidemiology, Biomarkers Serum Metabolic Profiling Identified a Distinct & Prevention Metabolic Signature in Bladder Cancer Smokers: A Key Metabolic Enzyme Associated with Patient Survival Chandra Sekhar Amara1, Chandrashekar R. Ambati2, Venkatrao Vantaku1, Danthasinghe Waduge Badrajee Piyarathna1, Sri Ramya Donepudi2, Shiva Shankar Ravi1, James M. Arnold3, Vasanta Putluri2, Gurkamal Chatta4, Khurshid A. Guru5, Hoda Badr6, Martha K. Terris7, Roni J. Bollag7, Arun Sreekumar1,3, Andrea B. Apolo8, and Nagireddy Putluri1 Abstract Background: The current system to predict the outcome of nylalanine, proline, serine, valine, isoleucine, glycine, and smokers with bladder cancer is insufficient due to complex asparagine) and taurine were observed in bladder cancer genomic and transcriptomic heterogeneities. This study aims smokers. Integration of differential metabolomic gene signa- to identify serum metabolite-associated genes related to sur- ture and transcriptomics data from TCGA cohort revealed an vival in this population. intersection of 17 genes that showed significant correlation Methods: We performed LC/MS-based targeted metabo- with patient survival in bladder cancer smokers. Importantly, lomic analysis for >300 metabolites in serum obtained catechol-O-methyltransferase, iodotyrosine deiodinase, and from two independent cohorts of bladder cancer never tubulin tyrosine ligase showed a significant association with smokers, smokers, healthy smokers, and healthy never patient survival in publicly available bladder cancer smoker smokers. A subset of differential metabolites was validated datasets and did not have any clinical association in never using Biocrates absoluteIDQ p180 Kit. Genes associated smokers. with differential metabolites were integrated with a publicly Conclusions: Serum metabolic profiling of bladder cancer available cohort of The Cancer Genome Atlas (TCGA) to smokers revealed dysregulated amino acid metabolism. It obtain an intersecting signature specific for bladder cancer provides a distinct gene signature that shows a prognostic smokers. value in predicting bladder cancer smoker survival. Results: Forty metabolites (FDR < 0.25) were identified to Impact: Serum metabolic signature–derived genes act as a be differential between bladder cancer never smokers and predictive tool for studying the bladder cancer progression in smokers. Increased abundance of amino acids (tyrosine, phe- smokers. Introduction Urinary bladder cancer is the ninth most common malignant 1Department of Molecular and Cell Biology, Baylor College of Medicine, Houston, disease and the 13th most common cause of cancer-related death Texas. 2Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center worldwide (1). Nearly 1.3 million people worldwide and 600,000 for Molecular Discovery, Baylor College of Medicine, Houston, Texas. 3Verna and in the United States alone are diagnosed with bladder cancer each Marrs McLean Department of Biochemistry and Molecular Biology, Baylor year contributing to a significant health care burden. Bladder College of Medicine, Houston, Texas. 4Department of Medicine, Roswell Park cancer has a high recurrence rate and requires lifelong surveillance Comprehensive Cancer Center, Buffalo, New York. 5Department of Urology, – Roswell Park Comprehensive Cancer Center, Buffalo, New York. 6Department of incurring major medical expenses (2 4). Occupational exposure Medicine, Baylor College of Medicine, Houston, Texas. 7Augusta University, to carcinogens has been long associated with increased bladder Augusta, Georgia. 8Center for Cancer Research, National Cancer Institute, cancer risk. Tobacco smoke contains more than 60 carcinogens Bethesda, Maryland. causing at least 18 different types of cancer including bladder Note: Supplementary data for this article are available at Cancer Epidemiology, cancer. Tobacco smoking is the best established risk factor for Biomarkers & Prevention Online (http://cebp.aacrjournals.org/). bladder cancer, with a population attributable risk for smoking of Corresponding Authors: Nagireddy Putluri, Baylor College of Medicine, One 50% for bladder cancer (5). More than 30% of people in the baylor Plaza, 120D, Houston, TX 77030. Phone: 713-798-3144; Fax: 713-798-1121; United States and Europe have a history of smoking (6), based on E-mail: [email protected]; and Andrea B. Apolo, Center for Cancer Research, which the patients with bladder cancer can be categorized into National Cancer Institute, 37 Convent Dr, Bethesda, MD 20814. E-mail: former and current smokers. Current smoking also increases the [email protected] risk of recurrence, drug resistance, and significantly increases the doi: 10.1158/1055-9965.EPI-18-0936 risk of death in bladder cancer compared with former and never Ó2019 American Association for Cancer Research. smokers (7, 8). Previous studies have suggested that smoking 770 Cancer Epidemiol Biomarkers Prev; 28(4) April 2019 Downloaded from cebp.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst January 14, 2019; DOI: 10.1158/1055-9965.EPI-18-0936 Smoke Affects Bladder Cancer Metabolism status and the quantity of smoking is associated with higher tumor contributing markers. These, in turn, can serve as prognostic and grade and stage in patients with bladder cancer (9). diagnostic biomarkers in the identification of disease and its Xenobiotic metabolizing enzymes expressed in the bladder pathogenesis (15). Although prior studies have successfully detoxify the genotoxic compounds and excrete them through utilized metabolomics for biomarker identification in bladder urine. It is known that alterations of xenobiotic enzymes are cancer sera (10, 16, 17), serum metabolic profiling for bladder associated with bladder cancer development (10, 11). Environ- cancer smokers is lacking. In this study, we applied targeted LC/ mental toxins, including the carcinogens from cigarettes, are MS approach to delineate serum-based biomarkers that differ- cleared by xenobiotic pathways and pass through the body's entiate patients with bladder cancer through smoking history excretion system. Over time, these products accumulate on the (current smokers, former smokers) from never smoking walls of the bladder, which, in turn, changes the genetic patients with bladder cancer. This study provides initial evi- composition of the bladder wall. Our group has previously dence of serum-based metabolite prognostic markers in blad- shown that tobacco-specific carcinogens alter metabolic path- dercancersmokers. ways and the expression levels of xenobiotic enzymes in blad- der cancer (12). Diagnostically, patients with bladder cancer are evaluated using cystoscopy, an endoscopic procedure per- Materials and Methods formed by urologist (13). Also, cells in the urine (cytology) Study population and serum profiling by LC/MS are inspected by trained cytopathologist to determine the In this study, serum samples from bladder cancer (n ¼ 67) were presence of cancer lesions in the bladder (14). However, the used from two independent cohorts: (i) NCI (n ¼ 59), (ii) Augusta sensitivity for bladder tumor detection with urine cytology University (Augusta, GA; n ¼ 8), Georgia Cancer Center and surveillance is low. Noninvasive procedures are needed for healthy case controls (n ¼ 20) from (iii) Baylor College of facilitating diagnostic, therapeutic, and prognostic strategies. Medicine (Houston, TX) procured by a prior written informed Unfortunately, to our knowledge, there are no diagnostic or consent under Institute review board–approved protocols. NCI surveillance serum- or plasma-associated metabolic biomarkers patient cohorts are enrolled in a clinical study with monotherapy that have been identified in bladder cancer smokers. cabozantinib. The advent of metabolic profiling with LC/MS has opened the A flow chart depicting the study overview, sample processing, possibilities to identify dysregulated metabolic pathways and and analysis are illustrated in Figure 1. (i) Serum (ii) after extraction Erythrocytes BLCA patients and normal individuals Control Control BLCA BLCA smokers never smokers current smokers never smokers former smokers (iii) Biochemical pathways (iv) Validation in TCGA and association with BLCA patient survival Figure 1. Overview of global serum metabolic profiling in patients with bladder cancer (BLCA) and normal individuals. The methodology involves four important steps: (i) serum extraction from blood samples of patients with bladder cancer and normal individuals, (ii) filtration, metabolic extraction, and targeted metabolic profiling by LC/MS, (iii) identification of differential metabolites and deciphering the biochemical pathways involving the upregulated metabolites, and (iv) validation of genes involved in regulating the biochemical pathways and their clinical association in TCGA cohorts. www.aacrjournals.org Cancer Epidemiol Biomarkers Prev; 28(4) April 2019 771 Downloaded from cebp.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst January 14, 2019; DOI: 10.1158/1055-9965.EPI-18-0936 Amara et al. Targeted metabolomics using mass spectrometry 250C; gas flow, 14 L/minute; Nebulizer, 20 psi; sheath gas Reagents and internal standards. High-performance liquid chro- temperature, 350 C; sheath gas flow, 12 L/minute; capillary, matography (HPLC)-grade ammonium acetate was from Sigma, 3,000 V positive and
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