Affiliations of authors: E. F. Petricoin III (Office of the Director/Center for Biologics Evaluation and Research), Food and Drug AdministrationNational Cancer Institute (FDANCI) Clinical Proteomics Program, FDA, National Institutes of Health (NIH), Bethesda, MD; L. A. Liotta, Laboratory of Pathology, Center for Cancer Research, FDANCI Clinical Proteomics Program, NCI, NIH, Bethesda.
Correspondence to: Emanuel F. Petricoin III, Ph.D., Bldg. 29A, Rm. 2D12, 8800 Rockville Pike, Bethesda, MD 20892 (e-mail: petricoin{at}cber.fda.gov).
We agree with Dr. Diamandis that the identity of the proteins comprising the discriminatory ions within the diagnostic proteomic pattern can potentially lead to insights concerning their source and relationship to the underlying pathology. However, the clinical evaluation of proteomic patterns as a new diagnostic paradigm can, and must, proceed independently from the pursuit of the physiologic source and identity of these proteins. Indeed, the characterization and identification of prostate-specific antigen (PSA) and CA 125 (for protein identification only) has had little impact on their ongoing utility and widespread clinical use as diagnostic cancer biomarkers.
Subsequent to our initial report in Lancet (1), a number of research groups have confirmed the diagnostic potential of serum proteomic patterns, as applied to a variety of cancers (24) and to our own ongoing efforts (5).
We hypothesize that the ion amplitudes comprising the diagnostic patterns in matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) spectra are derived (directly or indirectly) from the molecular state of the tumorhost microenvironment, and that the proteomic pattern that emanates from this microenvironment may signal the presence of an early-stage lesion. Under this hypothesis, the discriminatory ions are likely to be metabolic products, enzymatic fragments, modified proteins, peptides, or cytokines that could be highly specific for the microenvironment of the lesion.
Any plan to identify such ions must take into consideration two important issues. First, the amplitude of a given ion peak in a MALDI-TOF spectra is a complex result of the ionization pattern in the context of the matrix and the population of proteins and protein-binding partners in the sample that influence the ionization of each other. Thus, a peak amplitude value at a given m/z value cannot be equated to the concentration of a molecule (of that molecular size) in a serum sample. Second, an ion peak with high amplitude does not necessarily equate to a more abundant protein than one with a correspondingly low amplitude in the same spectral image; this concept is very important to understand.
Perhaps it is time to move beyond the presumption of the existence of a single cancer-specific biomarker. Because cancer cells are themselves deranged host cells, we may never find a "true" cancer-specific biomarker. Alternatively, the complex proteomic pattern of the tumorhost microenvironment may be unique and may constitute a biomarker amplification cascade. In fact, the most important biomarkers may be normal host proteins that are aberrantly clipped or reduced in abundance. A pattern analysis approach takes into consideration this loss or gain of ions within the spectra.
Depending on the identity of the discriminatory ion, it may or may not be desirable, or even feasible, to proceed directly to the development of a serum immunoassay for an individual biomarker. If the biomarker is the cleaved version of a larger protein, it may be difficult to generate antibodies that recognize the cleaved version but do not cross-react with the parent species.
Mass spectroscopy platforms of the future, coupled with heuristic pattern recognition algorithms, may become superior to immunoassays as clinical analyte sensors. Within seconds, mass spectroscopy can generate complex proteomic spectra from a small volume of bloodin effect, sensing the presence of hundreds to thousands of events simultaneously. Current mass spectroscopy platforms routinely achieve sensitivity in the femtomolar range and will become even more sensitive with improvements in the technology. As mass spectroscopy technology advances, it will be possible to obtain direct biomarker identification of diagnostic ions "on-the-fly."
Toward this goal, we are exploring a wide variety of mass spectroscopy platforms and tools. Mathematically, it should be obvious that a pattern of multiple biomarkers will contain a higher level of discriminatory information compared with that of a single biomarker, particularly for large heterogeneous patient populations. We are currently undertaking clinical trials to explore and validate this concept as applied to a variety of diseases. As evidence of the growing acceptance of this concept, large commercial laboratories have begun initiatives to explore mass spectroscopy proteomic patterns for routine diagnosis (6).
REFERENCES
1 Petricoin EF, Ardekani AM, Hitt BA, Levine PJ, Fusaro VA, Steinberg SM, et al. Use of proteomic patterns in serum to identify ovarian cancer. Lancet 2002;359:5727.[CrossRef][Medline]
2 Li J, Zhang Z, Rosenzweig J, Wang YY, Chan DW. Proteomics and bioinformatics approaches for identification of serum biomarkers to detect breast cancer. Clin Chem 2002;48:1296304.
3 Adam BL, Qu Y, Davis JW, Ward MD, Clements MA, Cazares LH, et al. Serum protein fingerprinting coupled with a pattern-matching algorithm distinguishes prostate cancer from benign prostate hyperplasia and healthy men. Cancer Res 2002;62:360914.
4 Qu Y, Adam BL, Yasui Y, Ward MD, Cazares LH, Schellhammer PF, et al. Boosted decision tree analysis of surface-enhanced laser desorption/ionization mass spectral serum profiles discriminates prostate cancer from noncancer patients. Clin Chem 2002;48:183543.
5 Petricoin EF III, Ornstein DK, Paweletz CP, Ardekani A, Hackett PS, Hitt BA, et al. Serum proteomic patterns for detection of prostate cancer. J Natl Cancer Inst 2002;94:15768.
6 Correlogic Systems Licenses Ovarian Cancer Diagnostic Test To Quest Diagnostics and LabCorpTM. Full press release available at: http://www.correlogic.com/questlabcorp_final.htm.
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