title: Metabolomic markers of altered nucleotide metabolism in early stage adenocarcinoma.
abstract: Adenocarcinoma, a type of non-small cell lung cancer, is the most frequently diagnosed lung cancer and the leading cause of lung cancer mortality in the United States. It is well documented that biochemical changes occur early in the transition from normal to cancer cells, but the extent to which these alterations affect tumorigenesis in adenocarcinoma remains largely unknown. Herein, we describe the application of mass spectrometry and multivariate statistical analysis in one of the largest biomarker research studies to date aimed at distinguishing metabolic differences between malignant and nonmalignant lung tissue. Gas chromatography time-of-flight mass spectrometry was used to measure 462 metabolites in 39 malignant and nonmalignant lung tissue pairs from current or former smokers with early stage (stage IA-IB) adenocarcinoma. Statistical mixed effects models, orthogonal partial least squares discriminant analysis and network integration, were used to identify key cancer-associated metabolic perturbations in adenocarcinoma compared with nonmalignant tissue. Cancer-associated biochemical alterations were characterized by (i) decreased glucose levels, consistent with the Warburg effect, (ii) changes in cellular redox status highlighted by elevations in cysteine and antioxidants, alpha- and gamma-tocopherol, (iii) elevations in nucleotide metabolites 5,6-dihydrouracil and xanthine suggestive of increased dihydropyrimidine dehydrogenase and xanthine oxidoreductase activity, (iv) increased 5'-deoxy-5'-methylthioadenosine levels indicative of reduced purine salvage and increased de novo purine synthesis, and (v) coordinated elevations in glutamate and UDP-N-acetylglucosamine suggesting increased protein glycosylation. The present study revealed distinct metabolic perturbations associated with early stage lung adenocarcinoma, which may provide candidate molecular targets for personalizing therapeutic interventions and treatment efficacy monitoring.
authors: University of California, Davis Genome Center, Davis, California.
authors: William R
authors: WR
authors: Wikoff
authors: University of California, Davis Genome Center, Davis, California.
authors: Dmitry
authors: D
authors: Grapov
authors: University of California, Davis Genome Center, Davis, California.
authors: Johannes F
authors: JF
authors: Fahrmann
authors: University of California, Davis Genome Center, Davis, California.
authors: Brian
authors: B
authors: DeFelice
authors: Division of Pulmonary, Critical Care and Sleep, New York University, School of Medicine New York, New York.
authors: William N
authors: WN
authors: Rom
authors: Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, New York.
authors: Harvey I
authors: HI
authors: Pass
authors: Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, California.
authors: Kyoungmi
authors: K
authors: Kim
authors: Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, California.
authors: UyenThao
authors: U
authors: Nguyen
authors: Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, California.
authors: Sandra L
authors: SL
authors: Taylor
authors: University of California, Davis Genome Center, Davis, California. Division of Pulmonary, Critical Care and Sleep, New York University, School of Medicine New York, New York. Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, New York. Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, California. Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California, Davis Medical Center, Sacramento, California. Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi-Arabia.
authors: David R
authors: DR
authors: Gandara
authors: Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California, Davis Medical Center, Sacramento, California.
authors: Karen
authors: K
authors: Kelly
authors: University of California, Davis Genome Center, Davis, California. Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi-Arabia.
authors: Oliver
authors: O
authors: Fiehn
authors: Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California, Davis Medical Center, Sacramento, California. smiyamoto@ucdavis.edu.
authors: Suzanne
authors: S
authors: Miyamoto
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism*; D042241:Early Diagnosis; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics; D008875:Middle Aged; D009367:Neoplasm Staging; D009711:Nucleotides / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D009711:Nucleotides
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