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Cancer Prev Res (Phila). 2015 May;8(5):410-8. doi: 10.1158/1940-6207.CAPR-14-0329. Epub 2015 Feb 5.

Metabolomic markers of altered nucleotide metabolism in early stage adenocarcinoma.

Author information

1
University of California, Davis Genome Center, Davis, California.
2
Division of Pulmonary, Critical Care and Sleep, New York University, School of Medicine New York, New York.
3
Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Langone Medical Center, New York University, New York, New York.
4
Division of Biostatistics, Department of Public Health Sciences, School of Medicine, University of California Davis, Davis, California.
5
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.
6
Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California, Davis Medical Center, Sacramento, California.
7
University of California, Davis Genome Center, Davis, California. Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi-Arabia.
8
Division of Hematology and Oncology, Department of Internal Medicine, School of Medicine, University of California, Davis Medical Center, Sacramento, California. smiyamoto@ucdavis.edu.

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.

PMID:
25657018
PMCID:
PMC4618700
DOI:
10.1158/1940-6207.CAPR-14-0329
[Indexed for MEDLINE]
Free PMC Article

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