Dataset Information

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.

SUBMITTER: Wikoff WR

PROVIDER: S-EPMC4618700 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Metabolomic markers of altered nucleotide metabolism in early stage adenocarcinoma.

Wikoff William R WR Grapov Dmitry D Fahrmann Johannes F JF DeFelice Brian B Rom William N WN Pass Harvey I HI Kim Kyoungmi K Nguyen UyenThao U Taylor Sandra L SL Gandara David R DR Kelly Karen K Fiehn Oliver O Miyamoto Suzanne S

Cancer prevention research (Philadelphia, Pa.) 20150205 5

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 bio ...[more]

PMID: 25657018

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Project description:Lung cancer has been the leading cause of cancer death in the United States and worldwide for many decades. Low dose spiral computerized tomography (LDCT) is likely to become the first approved screening and early detection test in the upcoming year, but it is plagued by a high false-positive rate. There is a need to develop complementary screening and early detection tools. A blood-based lung cancer signature is an attractive solution. Given that our knowledge of the molecular biology of smoking-induced lung cancer has dramatically increased over the past few years, this approach is plausible. To date, this effort has been focused on the identification of genomic and proteomic signatures with limited success. A broader strategy that incorporates additional cancer traits is needed. It is well recognized that wide coverage of cellular metabolism in cancer could help provide valuable diagnostic biomarkers and potentially identify molecular drivers of tumorigenesis. Recent advances in mass spectrometry have enabled comprehensive metabolomic analyses of lipids, carbohydrates, amino acids, and nucleotides within a variety of biologic matrices. Early evidence from metabolomic investigation of cancer has identified many altered biochemical profiles. However, to date, there have been few investigations of lung cancer, and most studies have looked at blood plasma or were limited by small sample sizes with mixed histologies. In the current investigation, gas chromatography time-offlight mass spectrometry (GC-TOF) was used to measure 462 lipid, carbohydrate, amino acid, organic acid, and nucleotide metabolites in 39 malignant and nonmalignant lung tissue pairs from current or former smokers with early stage adenocarcinoma. This study cohort represents patient characteristics and tumor histology most likely to be detected with LDCT screening. We hypothesize that identification of cancer-induced cellular and tissue level biochemical changes can offer a robust method for identification of candidate circulating biomarkers and improve our understanding of biochemical changes involved in adenocarcinoma tumorigenesis.

Project description:Glycation, oxidation, nitration, and crosslinking of proteins are implicated in the pathogenic mechanisms of type 2 diabetes, cardiovascular disease, and chronic kidney disease. Related modified amino acids formed by proteolysis are excreted in urine. We quantified urinary levels of these metabolites and branched-chain amino acids (BCAAs) in healthy subjects and assessed changes in early-stage decline in metabolic, vascular, and renal health and explored their diagnostic utility for a noninvasive health screen. We recruited 200 human subjects with early-stage health decline and healthy controls. Urinary amino acid metabolites were determined by stable isotopic dilution analysis liquid chromatography-tandem mass spectrometry. Machine learning was applied to optimise and validate algorithms to discriminate between study groups for potential diagnostic utility. Urinary analyte changes were as follows: impaired metabolic health-increased N ε -carboxymethyl-lysine, glucosepane, glutamic semialdehyde, and pyrraline; impaired vascular health-increased glucosepane; and impaired renal health-increased BCAAs and decreased N ε -(γ-glutamyl)lysine. Algorithms combining subject age, BMI, and BCAAs discriminated between healthy controls and impaired metabolic, vascular, and renal health study groups with accuracy of 84%, 72%, and 90%, respectively. In 2-step analysis, algorithms combining subject age, BMI, and urinary N ε -fructosyl-lysine and valine discriminated between healthy controls and impaired health (any type), accuracy of 78%, and then between types of health impairment with accuracy of 69%-78% (cf. random selection 33%). From likelihood ratios, this provided small, moderate, and conclusive evidence of early-stage cardiovascular, metabolic, and renal disease with diagnostic odds ratios of 6 - 7, 26 - 28, and 34 - 79, respectively. We conclude that measurement of urinary glycated, oxidized, crosslinked, and branched-chain amino acids provides the basis for a noninvasive health screen for early-stage health decline in metabolic, vascular, and renal health.

Project description:BACKGROUND:Several treatments in non-small cell lung cancer (NSCLC) are histology-dependent, and the need for histology-related markers is increasing. MicroRNAs (miRNAs) are promising molecular markers in multiple cancers and show differences in expression depending on histological subtype. The miRNA family miR-200 has been associated with the regulation of epithelial-mesenchymal (EMT)/mesenchymal-epithelial transition (MET). EMT involves profound phenotypic changes that include the loss of cell-cell adhesion, the loss of cell polarity, and the acquisition of migratory and invasive properties that facilitates metastasis. A dual role for the miR-200 family in the prognosis of several tumors has been related to tumor cell origin. However, the prognostic role and function of miR-200 family in early-stage NSCLC adenocarcinoma and squamous cell carcinoma (SCC) have not been well established. METHODS:miRNA expression was determined using TaqMan assays in 155 tumors from resected NSCLC patients. Functional studies were conducted in three NSCLC cell lines: H23, A-549 and HCC-44. RESULTS:High miR-200c expression was associated with shorter overall survival (OS) in the entire cohort (p?=?0.024). High miR-200c (p?=?0.0004) and miR-141 (p?=?0.009) expression correlated with shorter OS in adenocarcinoma - but not in SCC. In the multivariate analysis, a risk score based on miR-141 and miR-200c expression emerged as an independent prognostic factor for OS in the entire cohort (OR, 2.787; p?=?0.033) and in adenocarcinoma patients (OR, 10.649; p?=?0.002). Functional analyses showed that miR-200c, was related to mesenchymal-epithelial transition (MET) and affected cell migration and E-cadherin levels, while overexpression of miR-141 reduced KLF6 protein levels and produced an increase of secretion of VEGFA in vitro (H23, p?=?0.04; A-549, p?=?0.03; HCC-44, p?=?0.02) and was associated with higher blood microvessel density in patient tumor samples (p<0.001). CONCLUSION:High miR-141 and miR-200c expression are associated with shorter OS in NSCLC patients with adenocarcinoma through MET and angiogenesis.

Dataset Information

Metabolomic markers of altered nucleotide metabolism in early stage adenocarcinoma.

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Metabolomic markers of altered nucleotide metabolism in early stage adenocarcinoma.

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