Dataset Information

Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer.

ABSTRACT: Smoking is a major risk factor for the development of bladder cancer; however, the functional consequences of the carcinogens in tobacco smoke and bladder cancer-associated metabolic alterations remain poorly defined. We assessed the metabolic profiles in bladder cancer smokers and non-smokers and identified the key alterations in their metabolism. LC/MS and bioinformatic analysis were performed to determine the metabolome associated with bladder cancer smokers and were further validated in cell line models. Smokers with bladder cancer were found to have elevated levels of methylated metabolites, polycyclic aromatic hydrocarbons, DNA adducts, and DNA damage. DNA methyltransferase 1 (DNMT1) expression was significantly higher in smokers than non-smokers with bladder cancer. An integromics approach, using multiple patient cohorts, revealed strong associations between smokers and high-grade bladder cancer. In vitro exposure to the tobacco smoke carcinogens, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and benzo[a]pyrene (BaP) led to increase in levels of methylated metabolites, DNA adducts, and extensive DNA damage in bladder cancer cells. Cotreatment of bladder cancer cells with these carcinogens and the methylation inhibitor 5-aza-2'-deoxycytidine rewired the methylated metabolites, DNA adducts, and 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 bladder cancer smokers. Noninvasive predictive biomarkers that can stratify the risk of developing bladder cancer in smokers could aid in early detection and treatment. Cancer Prev Res; 10(10); 588-97. ©2017 AACR.

SUBMITTER: Jin F

PROVIDER: S-EPMC5626664 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer.

Jin Feng F Thaiparambil Jose J Donepudi Sri Ramya SR Vantaku Venkatrao V Piyarathna Danthasinghe Waduge Badrajee DWB Maity Suman S Krishnapuram Rashmi R Putluri Vasanta V Gu Franklin F Purwaha Preeti P Bhowmik Salil Kumar SK Ambati Chandrashekar R CR von Rundstedt Friedrich-Carl FC Roghmann Florian F Berg Sebastian S Noldus Joachim J Rajapakshe Kimal K Gödde Daniel D Roth Stephan S Störkel Stephan S Degener Stephan S Michailidis George G Kaipparettu Benny Abraham BA Karanam Balasubramanyam B Terris Martha K MK Kavuri Shyam M SM Lerner Seth P SP Kheradmand Farrah F Coarfa Cristian C Sreekumar Arun A Lotan Yair Y El-Zein Randa R Putluri Nagireddy N

Cancer prevention research (Philadelphia, Pa.) 20170829 10

Smoking is a major risk factor for the development of bladder cancer; however, the functional consequences of the carcinogens in tobacco smoke and bladder cancer-associated metabolic alterations remain poorly defined. We assessed the metabolic profiles in bladder cancer smokers and non-smokers and identified the key alterations in their metabolism. LC/MS and bioinformatic analysis were performed to determine the metabolome associated with bladder cancer smokers and were further validated in cell ...[more]

PMID: 28851690

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Project description:Epidemiological studies have linked aromatic amines (AAs) from tobacco smoke and some occupational exposures with bladder cancer risk. Several epidemiological studies have also reported a plausible role for structurally related heterocyclic aromatic amines present in tobacco smoke or formed in cooked meats with bladder cancer risk. DNA adduct formation is an initial biochemical event in bladder carcinogenesis. We examined paired fresh-frozen (FR) and formalin-fixed paraffin-embedded (FFPE) nontumor bladder tissues from 41 bladder cancer patients for DNA adducts of 4-aminobiphenyl (4-ABP), a bladder carcinogen present in tobacco smoke, and 2-amino-9 H-pyrido[2,3- b]indole, 2-amino-1-methyl-6-phenylimidazo[4,5- b]pyridine and 2-amino-3,8-dimethylimidazo[4,5- f]quinoxaline, possible human carcinogens, which occur in tobacco smoke and cooked meats. These chemicals are present in urine of tobacco smokers or omnivores. Targeted DNA adduct measurements were done by ultra-performance liquid chromatography-electrospray ionization multistage hybrid Orbitrap MS. N-(2'-Deoxyguanosin-8-yl)-4-ABP ( N-(dG-C8)-4-ABP) was the sole adduct detected in FR and FFPE bladder tissues. Twelve subjects (29%) had N-(dG-C8)-4-ABP levels above the limit of quantification, ranging from 1.4 to 33.8 adducts per 109 nucleotides (nt). DNA adducts of other human AA bladder carcinogens, including 2-naphthylamine (2-NA), 2-methylaniline (2-MA), 2,6-dimethylaniline (2,6-DMA), and lipid peroxidation (LPO) adducts, were screened for in bladder tissue, by our untargeted data-independent adductomics method, termed wide-selected ion monitoring (wide-SIM)/MS2. Wide-SIM/MS2 successfully detected N-(dG-C8)-4-ABP, N-(2'-deoxyadenosin-8-yl)-4-ABP and the presumed hydrazo linked adduct, N-(2'-deoxyguanosin- N2-yl)-4-ABP, and several LPO adducts in bladder DNA. Wide-SIM/MS2 detected multiple DNA adducts of 2-NA, 2-MA, and, 2,6-DMA, when calf thymus DNA was modified with reactive intermediates of these carcinogens. However, these AA-adducts were below the limit of detection in unspiked human bladder DNA (<1 adduct per 108 nt). Wide-SIM/MS2 can screen for many types of DNA adducts formed with exogenous and endogenous electrophiles and will be employed to identify DNA adducts of other chemicals that may contribute to the etiology of bladder cancer.

Project description:Aromatic amines and structurally related heterocyclic aromatic amines (HAAs) are produced during the combustion of tobacco or during the high-temperature cooking of meat. Exposure to some of these chemicals may contribute to the etiology of several common types of human cancers. 2-Amino-9H-pyrido[2,3-b]indole (A?C) is the most abundant HAA formed in mainstream tobacco smoke: it arises in amounts that are 25-100 times greater than the levels of the arylamine, 4-aminobiphenyl (4-ABP), a human carcinogen. 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is a prevalent HAA formed in cooked meats. A?C and MeIQx are rodent carcinogens; however, their carcinogenic potency in humans is unknown. A preliminary assessment of the carcinogenic potential of these HAAs in humans was conducted by examining the capacity of primary human hepatocytes to form DNA adducts of A?C and MeIQx, in comparison to 4-ABP, followed by the kinetics of DNA adduct removal by cellular enzyme repair systems. The principal DNA adducts formed were N-(deoxyguanosin-8-yl) (dG-C8) adducts. Comparable levels of DNA adducts were formed with A?C and 4-ABP, whereas adduct formation was ?5-fold lower for MeIQx. dG-C8-A?C and dG-C8-4-ABP were formed at comparable levels in a concentration-dependent manner in human hepatocytes treated with procarcinogens over a 10,000-fold concentration range (1 nM-10 ?M). Pretreatment of hepatocytes with furafylline, a selective inhibitor of cytochrome P450 1A2, resulted in a strong diminution of DNA adducts signifying that P450 1A2 is a major P450 isoform involved in bioactivation of these procarcinogens. The kinetics of adduct removal varied for each hepatocyte donor. Approximately half of the DNA adducts were removed within 24 h of treatment; however, the remaining lesions persisted over 5 days. The high levels of A?C present in tobacco smoke and its propensity to form persistent DNA adducts in human hepatocytes suggest that A?C can contribute to DNA damage and the risk of hepatocellular cancer in smokers.

Dataset Information

Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer.

Publications

Tobacco-Specific Carcinogens Induce Hypermethylation, DNA Adducts, and DNA Damage in Bladder Cancer.

Similar Datasets

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