Tobacco-specific carcinogens induce hypermethylation, DNA adducts and DNA damage in Bladder Cancer.

Smoking is a major risk factor for the development of Bladder Cancer (BLCA); however, the functional consequences of the carcinogens in tobacco smoke and BLCA-associated metabolic alterations remains poorly defined. We assessed the metabolic profiles in BLCA smokers and non-smokers, and identified the key alterations in their metabolism. Liquid Chromatography - Mass Spectrometry (LC-MS), and bioinformatic analysis were performed to determine the metabolome associated with BLCA smokers and were further validated in cell line models. Smokers with BLCA were found to have elevated levels of methylated metabolites, polycyclic aromatic hydrocarbons (PAHs), DNA adducts and DNA damage. DNA methyltransferase 1 (DNMT1) expression was significantly higher in smokers than non-smokers with BLCA. An integromics approach, using multiple patient cohorts, revealed strong associations between smokers and high-grade BLCA. In vitro exposure to the tobacco smoke carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BaP) led to increase in levels of methylated metabolites, DNA adducts, and extensive DNA damage in BLCA cells. Co-treatment of BLCA cells with these carcinogens and the methylation inhibitor 5-aza-2'-deoxycytidine (AZA) rewired the methylated metabolites, DNA adducts, DNA damage. These findings were confirmed through the isotopic labeled metabolic flux analysis. Screens using smoke associated metabolites and DNA adducts could provide robust biomarkers and improve individual risk prediction in BLCA smokers. Non-invasive predictive biomarkers that can stratify the risk of developing BLCA in smokers could aid in early detection and treatment.

Cancer prevention research (Philadelphia, Pa.). 2017 Aug 29 [Epub ahead of print]

Feng Jin, Jose Thaiparambil, Sri Ramya Donepudi, Venkat Rao Vantaku, Danthasinghe Waduge Badrajee Piyarathna, Suman Maity, Rashmi Krishnapuram, Vasanta Putluri, Franklin Gu, Preeti Purwaha, Salil Kumar Bhowmik, Chandra Shekar Reddy Ambati, Friedrich-Carl von Rundstedt, Florian Roghmann, Sebastian Berg, Joachim Noldus, Kimal Rajapakshe, Daniel Gödde, Stephan Roth, Stephan Störkel, Stephan Degener, George Michailidis, Benny A Kaipparettu, Balasubramanyam Karanam, Martha K Terris, Shyam M Kavuri, Seth P Lerner, Farrah Kheradmand, Cristian Coarfa, Arun Sreekumar, Yair Lotan, Randa El-Zein, Nagireddy Putluri

Dan L. Duncan Cancer Center, Advanced Technology Core, Alkek Center for Molecular Discovery, Baylor College of Medicine., Department of Radiology, Houston Methodist Research Institute., Molecular and Cellular Biology, Baylor College of Medicine., Department of Molecular and Cell Biology, Baylor College of Medicine., Department of Molecular and Cell Biology, Baylor college of Medicine., Scott Department of Urology, Baylor College of Medicine., Marien Hospital, Ruhr-University Bochum, Marien Hospital, Ruhr-University Bochum., Department of Urology, Marien Hospital, Ruhr-University Bochum., Marien Hospital, Ruhr-University Bochum., Department of Pathology, Witten-Herdecke University., Department of Urology Helios Klinikum, Witten-Herdecke University., University of Florida., Department of Molecular and Human Genetics, Baylor College of Medicine., Department of Biology and Center for Cancer Research, Tuskegee University., Augusta University., Lester and Sue Smith Breast Center, Baylor College of Medicine., Urology, Baylor College of Medicine., Baylor College of Medicine., Department of Molecular and Cell Biology, Verna and Marrs McLean Department of Biochemistry, Baylor College of Medicine., Department of Urology, University of Texas Southwestern., Molecular and Cellular Biology, Verna and Marrs McLean Department of Biochemistry, Alkek Center for Molecular Discovery, Baylor College of Medicine .