Cancer Diagnostics Using 1H-NMR-Based Metabonomics

Conference paper
Part of the Ernst Schering Foundation Symposium Proceedings book series (SCHERING FOUND, volume 2007/4)


For several solid human malignancies, currently available serum biomarkers are insufficiently reliable to distinguish patients from healthy individuals. Metabonomics, the study of metabolic processes in biologic systems, is based on the use of 1H-NMR spectroscopy and multivariate statistics for biochemical data generation and interpretation and may provide a characteristic fingerprint in disease. Here we review our initial experiences utilizing the metabonomic approach for discriminating sera from women with epithelial ovarian cancer (EOC) from healthy controls. 1H-NMR spectroscopic analysis was performed on preoperative serum specimens of 38 EOC patients, 12 patients with benign ovarian cysts and 53 healthy women. PCA analysis allowed correct separation of all serum specimens from 38 patients with EOC (100%) from all of the 21 premenopausal normal samples (100%) and from all the sera from patients with benign ovarian disease (100%). In addition, it was possible to correctly separate 37 of 38 (97.4%) cancer specimens from 31 of 32 (97%) postmenopausal control sera. ROC analysis indicated that the sera from patients with and without disease could be identified with 100% sensitivity and specificity at the 1H-NMR regions 2.77 parts per million (ppm) and 2.04 ppm from the origin (AUC of ROC curve = 1.0). These findings indicate that the 1H-NMR metabonomic approach deserves further evaluation as a potential novel strategy for the early detection of EOC.


Epithelial Ovarian Cancer Principal Component Analysis Model Epithelial Ovarian Cancer Patient Receiver Operate Characteristic Curve Analysis Receiver Operate Characteristic Curve Curve 



I thank Dr. Thomas Szyperski for helpful discussions. Supported by the Oshei Foundation, Roswell Park Cancer Center Support Grant P30CA16056 and R21 CA106949–01A1 from the National Institutes of Health.


  1. Ala-Korpela M (1995) 1H-NMR spectroscopy of human blood plasma. Prog Nucl Magn Reson Spectrosc 27:475–554CrossRefGoogle Scholar
  2. Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA (2006) Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354:34–43CrossRefPubMedGoogle Scholar
  3. Bast RC Jr, Klug TL, St John E, Jenison E, Niloff JM, Lazarus H, Berkowitz RS, Leavitt T, Griffiths CT, Parker L, Zurawski VR Jr, Knapp RC (1983) A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309:883–887CrossRefPubMedGoogle Scholar
  4. Berek JS, Bast RC Jr (1995) Ovarian cancer screening. The use of serial complementary tumor markers to improve sensitivity and specificity for early detection. Cancer 76:2092–2096CrossRefPubMedGoogle Scholar
  5. Brindle JT, Antti H, Holmes E, Tranter G, Nicholson JK, Bethell HW, Clarke S, Schofield PM, McKilligin E, Mosedale DE, Grainger DJ (2002) Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nat Med 8:1439–1444CrossRefPubMedGoogle Scholar
  6. Brindle JT, Nicholson JK, Schofield PM, Grainger DJ, Holmes E (2003) Application of chemometrics to 1H NMR spectroscopic data to investigate a relationship between human serum metabolic profiles and hypertension. Analyst 128:32–36CrossRefPubMedGoogle Scholar
  7. Chmurny GN, Hilton BD, Halverson D, McGregor GN, Klose J, Issaq HJ, Muschik GM, Urba WJ, Mellini ML, Costello R et al (1988) An NMR blood test for cancer: a critical assessment. NMR Biomed 1:136–150CrossRefPubMedGoogle Scholar
  8. Coomans D, Broeckaert I, Derde MP, Tassin A, Massart DL, Wold S (1984) Use of a microcomputer for the definition of multivariate confidence regions in medical diagnosis based on clinical laboratory profiles. Comput Biomed Res 17:1–14CrossRefPubMedGoogle Scholar
  9. Denkert C, Budczies J, Kind T, Weichert W, Tablack P, Sehouli J, Niesporek S, Konsgen D, Dietel M, Fiehn O (2006) Mass spectrometry-based metabolic profiling reveals different metabolite patterns in invasive ovarian carcinomas and ovarian borderline tumors. Cancer Res 66:10795–10804CrossRefPubMedGoogle Scholar
  10. Dorum A, Kristensen GB, Abeler VM, Trope CG, Moller P (1996) Early detection of familial ovarian cancer. Eur J Cancer 32A:1645–1651CrossRefPubMedGoogle Scholar
  11. Eriksson L, Johansson E, Kettaneh-Wold N, Wold S (1999) Introduction to multi- and megavariate data analysis using projection methods (PCA, PLS) Umetrics, Umea, SwedenGoogle Scholar
  12. Fossel ET, Carr JM, McDonagh J (1986) Detection of malignant tumors. Water-suppressed proton nuclear magnetic resonance spectroscopy of plasma. N Engl J Med 315:1369–1376CrossRefPubMedGoogle Scholar
  13. Fures R, Bukovic D, Hodek B, Klaric B, Herman R, Grubisic G (1999) Preoperative tumor marker CA125 levels in relation to epithelial ovarian cancer stage. Coll Antropol 23:189–194PubMedGoogle Scholar
  14. Gavaghan CL, Holmes E, Lenz E, Wilson ID, Nicholson JK (2000) An NMR-based metabonomic approach to investigate the biochemical consequences of genetic strain differences: application to the C57BL10J, Alpk:ApfCD mouse. FEBS Lett 484:169–174CrossRefPubMedGoogle Scholar
  15. Greenlee RT, Hill-Harmon MB, Murray T, Thun M (2001) Cancer statistics, 2001. CA Cancer J Clin 51:15–36CrossRefPubMedGoogle Scholar
  16. Holmes E, Nicholson JK, Tranter G (2001) Metabonomic characterization of genetic variations in toxicological and metabolic responses using probabilistic neural networks. Chem Res Toxicol 14:182–191CrossRefPubMedGoogle Scholar
  17. Jacobs IJ, Skates SJ, MacDonald N, Menon U, Rosenthal AN, Davies AP, Woolas R, Jeyarajah AR, Sibley K, Lowe DG, Oram DH (1999) Screening for ovarian cancer: a pilot randomised controlled trial. Lancet 353:1207–1210CrossRefPubMedGoogle Scholar
  18. Kim JH, Skates SJ, Uede T, Wong KK, Schorge JO, Feltmate CM, Berkowitz RS, Cramer DW, Mok SC (2002) Osteopontin as a potential diagnostic biomarker for ovarian cancer. JAMA 287:1671–1679CrossRefPubMedGoogle Scholar
  19. Lemaire R, Menguellet SA, Stauber J, Marchaudon V, Lucot JP, Collinet P, Farine MO, Vinatier D, Day R, Ducoroy P, Salzet M, Fournier I (2007) Specific MALDI imaging and profiling for biomarker hunting and validation: fragment of the 11S proteasome activator complex reg alpha fragment is a new potential ovary cancer biomarker. J Proteome Res 6:4127–4134CrossRefPubMedGoogle Scholar
  20. Lindon JC, Nicholson JK, Everett JR (1999) NMR spectroscopy of biofluids. Annu Rep NMR Spectrosc 38:1–88CrossRefGoogle Scholar
  21. Lindon JC, Nicholson JK, Holmes E, Everett JR (2000) Metabonomics: metabolic processes studied by NMR spectroscopy of biofluids. Concepts Magn Reson 12:289–320CrossRefGoogle Scholar
  22. Lindon JC, Holmes E, Nicholson JK (2001) Pattern recognition methods and applications in biomedical magnetic resonance. Prog Nucl Magn Reson Spectrosc 39:1–40CrossRefGoogle Scholar
  23. Liotta LA, Kohn EC (2001) The microenvironment of the tumour-host interface. Nature 411:375–379CrossRefPubMedGoogle Scholar
  24. McGuire WP, Hoskins WJ, Brady MF, Kucera PR, Partridge EE, Look KY, Clarke-Pearson DL, Davidson M (1996) Cyclophosphamide and cisplatin versus paclitaxel and cisplatin: a phase III randomized trial in patients with suboptimal stage III/IV ovarian cancer (from the Gynecologic Oncology Group). Semin Oncol 23:40–47PubMedGoogle Scholar
  25. McIntosh MW, Urban N, Karlan B (2002) Generating longitudinal screening algorithms using novel biomarkers for disease. Cancer Epidemiol Biomarkers Prev 11:159–166PubMedGoogle Scholar
  26. McIntosh MW, Liu Y, Drescher C, Urban N, Diamandis EP (2007) Validation and characterization of human kallikrein 11 as a serum marker for diagnosis of ovarian carcinoma. Clin Cancer Res 13:4422–4428CrossRefPubMedGoogle Scholar
  27. Menon U, Jacobs IJ (2000) Recent developments in ovarian cancer screening. Curr Opin Obstet Gynecol 12:39–42CrossRefPubMedGoogle Scholar
  28. Nicholson JK, Wilson ID (1989) High resolution proton magnetic resonance spectroscopy of biological fluids. Prog Nucl Magn Reson Spectrosc 21:449–501CrossRefGoogle Scholar
  29. Nicholson JK, Foxall PJ, Spraul M, Farrant RD, Lindon JC (1995) 750 MHz 1H and 1H-13C NMR spectroscopy of human blood plasma. Anal Chem 67:793–811CrossRefPubMedGoogle Scholar
  30. Nicholson JK, Lindon JC, Holmes E (1999) `Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 29:1181–1189CrossRefPubMedGoogle Scholar
  31. Nicholson JK, Connelly J, Lindon JC, Holmes E (2002) Metabonomics: a platform for studying drug toxicity and gene function. Nat Rev Drug Discov 1:153–161CrossRefPubMedGoogle Scholar
  32. Odunsi K, Wollman RM, Ambrosone CB, Hutson A, McCann SE, Tammela J, Geisler JP, Miller G, Sellers T, Cliby W, Qian F, Keitz B, Intengan M, Lele S, Alderfer JL (2005) Detection of epithelial ovarian cancer using 1H-NMR-based metabonomics. Int J Cancer 113:782–788CrossRefPubMedGoogle Scholar
  33. Pepe MS (1997) A regression modeling framework for receiver operating characteristic curves in medical diagnostic testing. Biometrika 84:595–608CrossRefGoogle Scholar
  34. Pretsch E, Seibl J, Simon W, Clerc T (1989) Spectral data for structure determination of organic compounds. Springer-Verlag, Berlin Heidelberg New YorkGoogle Scholar
  35. Reviews E (2003) Database of abstracts of reviews of effects NHS Centre for Reviews and Dissemination. Screening for ovarian cancer. Database of Absracts of Reviews of EffectivenessGoogle Scholar
  36. Skates SJ, Xu FJ, Yu YH, Sjovall K, Einhorn N, Chang Y, Bast RC Jr, Knapp RC (1995) Toward an optimal algorithm for ovarian cancer screening with longitudinal tumor markers. Cancer 76:2004–2010CrossRefPubMedGoogle Scholar
  37. Skates SJ, Menon U, MacDonald N, Rosenthal AN, Oram DH, Knapp RC, Jacobs IJ (2003) Calculation of the risk of ovarian cancer from serial CA-125 Values for preclinical detection in postmenopausal women. J Clin Oncol 21:206–210CrossRefGoogle Scholar
  38. Suzuki M, Ohwada M, Aida I, Tamada T, Hanamura T, Nagatomo M (1993) Macrophage colony-stimulating factor as a tumor marker for epithelial ovarian cancer. Obstet Gynecol 82:946–950CrossRefPubMedGoogle Scholar
  39. van Nagell JR Jr, DePriest PD, Reedy MB, Gallion HH, Ueland FR, Pavlik EJ, Kryscio RJ (2000) The efficacy of transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer. Gynecol Oncol 77:350–356CrossRefPubMedGoogle Scholar
  40. Wingo PA, Tong T, Bolden S (1995) Cancer statistics, 1995. CA Cancer J Clin 45:8–30CrossRefPubMedGoogle Scholar
  41. Wold S, Antti H, Lindgren F, Ohman J (1998) Orthogonal signal correction of near-infrared spectra. Chemom Intell Lab Syst 44:175–185CrossRefGoogle Scholar
  42. Xu Y, Shen Z, Wiper DW, Wu M, Morton RE, Elson P, Kennedy AW, Belinson J, Markman M, Casey G (1998) Lysophosphatidic acid as a potential biomarker for ovarian and other gynecologic cancers. JAMA 280:719–723CrossRefPubMedGoogle Scholar
  43. Young RC, Walton LA, Ellenberg SS, Homesley HD, Wilbanks GD, Decker DG, Miller A, Park R, Major F Jr (1990) Adjuvant therapy in stage I and stage II epithelial ovarian cancer. Results of two prospective randomized trials. N Engl J Med 322:1021–1027CrossRefPubMedGoogle Scholar
  44. Zhang Z, Barnhill SD, Zhang H, Xu F, Yu Y, Jacobs I, Woolas RP, Berchuck A, Madyastha KR, Bast RC Jr (1999) Combination of multiple serum markers using an artificial neural network to improve specificity in discriminating malignant from benign pelvic masses. Gynecol Oncol 73:56–61CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2008

Authors and Affiliations

  1. 1.Departments of Gynecologic and Oncology ImmunologyRoswell Park Cancer InstituteBuffaloUSA

Personalised recommendations