Metabonomic models of human pancreatic cancer using 1D proton NMR spectra of lipids in plasma

In this study, we hypothesized that the altered insulin and glucose levels in male pancreatic cancer patients reported in a recent JAMA article would result in an altered lipid profile in the blood of pancreatic cancer patients when compared to controls (Stolzenberg-Solomon et al., 2005). Proton nuclear magnetic resonance (NMR) spectra of human lipophilic plasma extracts were used in order to build partial least squares discriminant function (PLS-DF) models that classified samples as belonging to the pancreatic control group or to the pancreatic cancer group. The sensitivity, specificity, and overall accuracy of the PLS-DF models based on 4 bins were 96%, 88%, and 92%, respectively. The sensitivity, specificity, and overall accuracy of the PLS-DF models based on 5 bins were 98%, 94%, and 96%, respectively. The sensitivity, specificity and overall accuracy of both the 4-bin and 5-bin PLS-DF models dropped only 1–2% during leave-25%-out cross-validation testing. Mass spectrometric profiling of phospholipids in plasma found three phosphatidylinositols that were significantly lower in pancreatic cancer patients than in healthy controls. The cancer models are based upon changes in lipid profiles that may provide a more sensitive and accurate diagnosis of pancreatic cancer than current methods that are based upon a single biomarker.

[1]  D. E. Patterson,et al.  Crossvalidation, Bootstrapping, and Partial Least Squares Compared with Multiple Regression in Conventional QSAR Studies , 1988 .

[2]  Richard D. Beger,et al.  Discriminant Function Analyses of Liver-Specific Carcinogens , 2004, J. Chem. Inf. Model..

[3]  Donald G Robertson,et al.  Metabonomics in toxicology: a review. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[4]  Guowang Xu,et al.  Discrimination of Type 2 diabetic patients from healthy controls by using metabonomics method based on their serum fatty acid profiles. , 2004, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[5]  H. Thomas,et al.  Proton and phosphorus-31 nuclear magnetic resonance spectroscopy of human bile in hepatopancreaticobiliary cancer , 2005, European journal of gastroenterology & hepatology.

[6]  J. Bruce German,et al.  Lipid metabolome-wide effects of the PPARγ agonist rosiglitazones⃞s The online version of this article (available at http://www.jlr.org) contains an additional 4 tables. Published, JLR Papers in Press, August 16, 2002. DOI 10.1194/jlr.M200169-JLR200 , 2002, Journal of Lipid Research.

[7]  Jianren Gu,et al.  Plasma phospholipid metabolic profiling and biomarkers of type 2 diabetes mellitus based on high-performance liquid chromatography/electrospray mass spectrometry and multivariate statistical analysis. , 2005, Analytical chemistry.

[8]  Qing Yang,et al.  Diagnosis of liver cancer using HPLC-based metabonomics avoiding false-positive result from hepatitis and hepatocirrhosis diseases. , 2004, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[9]  Takao Shimizu,et al.  Focused lipidomics by tandem mass spectrometry. , 2005, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[10]  C. Abiaka,et al.  Serum antioxidant and cholesterol levels in patients with different types of cancer , 2001, Journal of clinical laboratory analysis.

[11]  Z. Figaszewski,et al.  Changes in electric charge and phospholipids composition in human colorectal cancer cells , 2005, Molecular and Cellular Biochemistry.

[12]  H. Issaq,et al.  An NMR blood test for cancer: a critical assessment , 1988, NMR in biomedicine.

[13]  D. Albanes,et al.  Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers. , 2005, JAMA.

[14]  G. van Meer,et al.  Cellular lipidomics , 2005, The EMBO journal.

[15]  T. Poon,et al.  Proteome analysis and its impact on the discovery of serological tumor markers. , 2001, Clinica chimica acta; international journal of clinical chemistry.

[16]  W. Lehmann,et al.  Quantitative analysis of biological membrane lipids at the low picomole level by nano-electrospray ionization tandem mass spectrometry. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[17]  J. M. Carr,et al.  Detection of malignant tumors. Water-suppressed proton nuclear magnetic resonance spectroscopy of plasma. , 1986, The New England journal of medicine.

[18]  Martin Hermansson,et al.  Automated quantitative analysis of complex lipidomes by liquid chromatography/mass spectrometry. , 2005, Analytical chemistry.

[19]  T. Baillie,et al.  Drug metabolites in safety testing. , 2002, Toxicology and applied pharmacology.

[20]  Y. Miura,et al.  Serum lipid levels correlate with solid tumor weight in hepatoma-bearing rats fed dietary fish oil. , 2004, Journal of nutritional science and vitaminology.

[21]  Robert S Plumb,et al.  Metabonomics: the use of electrospray mass spectrometry coupled to reversed-phase liquid chromatography shows potential for the screening of rat urine in drug development. , 2002, Rapid communications in mass spectrometry : RCM.

[22]  M. D'Angelica,et al.  Intraductal Papillary Mucinous Neoplasms of the Pancreas: An Analysis of Clinicopathologic Features and Outcome , 2004, Annals of surgery.

[23]  D. Klimstra,et al.  Intraductal papillary‐mucinous neoplasms of the pancreas , 2002, Cancer.

[24]  Markus R. Wenk,et al.  The emerging field of lipidomics , 2005 .

[25]  F. Podo Tumour phospholipid metabolism , 1999, NMR in biomedicine.

[26]  Xianlin Han,et al.  Shotgun lipidomics: electrospray ionization mass spectrometric analysis and quantitation of cellular lipidomes directly from crude extracts of biological samples. , 2005, Mass spectrometry reviews.

[27]  D. Kell,et al.  Metabolic profiling using direct infusion electrospray ionisation mass spectrometry for the characterisation of olive oils. , 2002, The Analyst.

[28]  M. Krzyżanowski,et al.  Elevated tumor marker CA 19-9 in the differential diagnosis of pancreatic mass lesions. , 2004, Annales Universitatis Mariae Curie-Sklodowska. Sectio D: Medicina.

[29]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[30]  Alan Hutson,et al.  Detection of epithelial ovarian cancer using 1H‐NMR‐based metabonomics , 2005, International journal of cancer.

[31]  S. Shiesh,et al.  The value of biliary amylase and Hepatocarcinoma-Intestine-Pancreas/Pancreatitis-associated Protein I (HIP/PAP-I) in diagnosing biliary malignancies. , 2005, Clinical biochemistry.

[32]  S. Gourgiotis,et al.  Intraductal papillary mucinous neoplasms of the pancreas. , 2007, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[33]  J. Lindon,et al.  Metabonomics: a platform for studying drug toxicity and gene function , 2002, Nature Reviews Drug Discovery.

[34]  T. Kieber‐Emmons,et al.  1H-NMR metabonomics analysis of sera differentiates between mammary tumor-bearing mice and healthy controls , 2005, Metabolomics.

[35]  Anthony F. P. Nash,et al.  A 1H NMR-based metabonomic study of urine and plasma samples obtained from healthy human subjects. , 2003, Journal of pharmaceutical and biomedical analysis.

[36]  Henrik Antti,et al.  Contemporary issues in toxicology the role of metabonomics in toxicology and its evaluation by the COMET project. , 2003, Toxicology and applied pharmacology.

[37]  Royston Goodacre,et al.  Application of high-throughput Fourier-transform infrared spectroscopy in toxicology studies: contribution to a study on the development of an animal model for idiosyncratic toxicity. , 2004, Toxicology letters.

[38]  Manal M. Hassan,et al.  Polymorphisms of cytochrome P4501A2 and N-acetyltransferase genes, smoking, and risk of pancreatic cancer. , 2006, Carcinogenesis.

[39]  Richard D. Beger,et al.  NMR-based metabonomic evaluation of livers from rats chronically treated with tamoxifen, mestranol, and phenobarbital , 2005, Metabolomics.

[40]  Philip Jonathan,et al.  On the use of cross-validation to assess performance in multivariate prediction , 2000, Stat. Comput..

[41]  D. Yoon,et al.  Clinical Significance of p16 Protein Expression Loss and Aberrant p53 Protein Expression in Pancreatic Cancer , 2005, Yonsei medical journal.

[42]  V. L. Doyle,et al.  Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy , 2003, Magnetic resonance in medicine.

[43]  K. Syrigos,et al.  Evaluation of serum lipids and high-density lipoprotein subfractions (HDL2, HDL3) in postmenopausal patients with breast cancer , 2005, Molecular and Cellular Biochemistry.

[44]  E Holmes,et al.  NMR spectroscopy based metabonomic studies on the comparative biochemistry of the kidney and urine of the bank vole (Clethrionomys glareolus), wood mouse (Apodemus sylvaticus), white toothed shrew (Crocidura suaveolens) and the laboratory rat. , 2000, Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology.

[45]  杨军,et al.  Plasma Phospholipid Metabolic Profiling and Biomarkers of Type 2 Diabetes Mellitus Based on High Performance Liquid Chromatography/Electrospray Mass Spectrometry and Multivariate Statistical Analysis , 2005 .

[46]  J. Nicholson,et al.  Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics , 2002, Nature Medicine.

[47]  J Bruce German,et al.  Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone. , 2002, Journal of lipid research.

[48]  I. Wilson,et al.  Understanding 'Global' Systems Biology: Metabonomics and the Continuum of Metabolism , 2003, Nature Reviews Drug Discovery.

[49]  G. Meer New EMBO Member's Review Cellular lipidomics , 2005 .

[50]  G. Mills,et al.  Lysophosphatidic acid production and action: Validated targets in cancer? , 2004, Journal of cellular biochemistry.