Editorial

Mass Spectrometry-based Diagnostics:

The Upcoming Revolution in Disease Detection
Advances in mass spectrometry-based diagnostics could extremely well-characterized, high-affinity antibody for
ignite a revolution in the field of molecular medicine. This detection of the analyte. This requires a tremendous
platform has the potential to become the practical clinical amount of time and effort. Traditionally, the search for
analyzer of the future for nucleic acids and proteins. Mass cancer-related biomarkers for early disease detection,
spectrometry-based diagnostics are an example of a “dis- aggressiveness, and therapeutic response has been a one-
ruptive” or “nonlinear” technology (1, 2 ). Such disruptive at-a-time approach looking for overexpressed proteins in
technologies are by their very nature polarizing, causing a blood that are shed into the circulation as a consequence
dynamic dichotomy of excitement (3 ) as well as anxiety of the disease process (12–14 ). Unfortunately, this ap-

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(4 ) in the clinical diagnostic community because this proach is laborious and time-consuming because there are
technology can potentially outperform traditional mea- potentially thousands of intact and cleaved proteins in the
surement and detection systems. In this issue of Clinical human serum proteome that would need to be identified,
Chemistry, Bonk et al. (5 ) demonstrate the advantages of and antibodies would need to be developed, validated,
mass spectrometry compared with traditional electro- and checked for specificity and sensitivity. Finding the
phoretic methodologies. Bonk et al. used mass spectrom- single disease-related protein is like searching for a needle
etry as a “sensor” to detect the amplified product from a in a haystack, requiring the separation and identification
PCR amplification reaction. The ultimate clinical applica- of these entities one by one. Moreover, it is likely that
tion for this study is the early detection of colon cancer, a discovery and use of the elusive single biomarkers for
topic of obvious public health importance. early detection of cancer will be nonexistent because
Although major advances have been made in elucidat- clinical applications would be applied to a human popu-
ing the genetic underpinnings of cancer, especially colo- lation characterized by vast heterogeneity not only in
rectal cancer, diagnostic methodologies for routine clini- their proteomes, but also in the underlying cancer genet-
cal detection and monitoring of important cancer genetic ics.
derangements have lagged behind. Microsatellite instabil- Within the past year, a new type of protein-based
ity (MSI), caused by mismatch repair gene silencing, is diagnostic paradigm has been described: proteomic pat-
predicted to be an important early event in cancer pro- tern diagnostics (15 ). With this approach, a single droplet
gression (6 – 8 ). of blood is placed on a specially treated surface that
In this issue, Bonk et al. (5 ) report on a study in which contains chemical bait molecules that bind with proteins
they use time-of-flight-based mass spectrometry to detect in the blood. The surface is washed and subjected to
MSI. Unlike previous studies, in which chromatography, MALDI-TOF analysis. The readout is a proteomic “bar-
electrophoresis, and traditional DNA sequencing method- code” pattern of the complex protein milieu that sticks to
ologies were used to detect the presence of MSI, these the surface. A typical low-resolution MALDI-TOF pro-
authors have chosen a technology that has many distinct teomic profile will have up to 15 500 data points that
advantages over these more traditional methods. As comprise the recordings of data between m/z 500 and
pointed out by the authors, these traditional methods are 20 000, with higher resolution mass spectrometry instru-
really not amenable to high-throughput diagnostics be- ments generating as many as 400 000 data points for m/z
cause they are low throughput, costly, and suffer from 500 to 12 000.
poor sensitivity. Mass spectrometry, on the other hand, is Proteomic pattern diagnostics use new types of pattern
extremely rapid (the entire process can occur in less than recognition systems to sift through this huge amount of
1 min), has tremendous cycle time (hundreds of samples data to find diagnostic patterns of protein expression.
can be analyzed sequentially, one after another without These artificial-intelligence-based bioinformatic systems
pause), and can achieve sensitivities in the femtomolar are vigilant and powerful, and enable the analysis of these
range (9 –11 ). After PCR amplification, Bonk et al. (5 ) large, complex datastreams. These types of informatic
used matrix-assisted laser desorption/ionization time-of- algorithms have the special attribute to learn, adapt, and
flight (MALDI-TOF) mass spectrometry to directly detect gain experience over time and are uniquely suited for
the PCR products. proteomic data analysis because of the huge dimension-
Mass spectrometry-based detection of surrogates for ality of the proteome itself. The artificial intelligence tool
disease detection is a timely topic. Mass spectrometry has learns, adapts, and gains experience through constant
recently generated excitement (and anxiety) as a platform vigilant retraining—meaning that it can start to recognize
for protein-based biomarker profiling. The most reliable, a unique and new phenotype that the system had not
sensitive, and widely available tests for the detection of been trained to recognize or even seen before. This is
cancer today are protein–ligand assays, such as ELISA extremely important when one considers clinical applica-
systems. These tests are robust, linear, accurate, and have tions involving the screening of hundreds of thousands of
reasonable throughput. However, the use of an ELISA patients. In fact, it is possible to generate not just one, but
system to test for the presence of disease requires a single, multiple combinations of proteomic patterns with diag-
meticulously validated analyte for detection as well as an nostic potential (16 ). With this approach, knowledge of

Clinical Chemistry 49, No. 4, 2003 533

534 Petricoin and Liotta: Mass Spectrometry-based Diagnostics

the underlying identities of the individual components of 4. Diamandis EP. Proteomic patterns in serum and identification of ovarian
cancer [Letter]. Lancet 2002;360:170.
the pattern is not necessary for its use as a potential 5. Bonk T, Humeny A, Gebert J, Sutter C, von Knebel Doeberitz M, Becker C-M.
diagnostic and sentinel for the presence of the disease: the Matrix-assisted laser desorption/ionization time-of-flight mass spectrome-
pattern itself is the diagnostic. try-based detection of microsatellite instabilities in coding DNA sequences:
a novel approach to identify DNA-mismatch repair-deficient cancer cells. Clin
Mass spectrometry-based proteomic pattern diagnos- Chem 2003;49:552– 61.
tics have been used for ovarian cancer detection, and the 6. Jass JR, Whitehall VL, Young J, Leggett BA. Emerging concepts in colorectal
value of this paradigm has been confirmed in other neoplasia. Gastroenterology 2002;123:862–76.
7. Haydon AM, Jass JR. Emerging pathways in colorectal-cancer development.
diseases, including breast (17 ) and prostate cancer Lancet Oncol 2002;3:83– 8.
(18, 19 ). What this means is that the unique tumor– host 8. Starostik P, Muller-Hermelink HK. Diagnosis of microsatellite instability-
positive colorectal cancer. Expert Rev Mol Diagn 2001;1:71– 80.
microenvironment can set off amplification cascades that 9. McDonald WH, Yates JR 3rd. Shotgun proteomics and biomarker discovery.
may be specific to the disease process, and yet the Dis Markers 2002;18:99 –105.
signatures for the presence of cancer, even at its earliest 10. Bonk T, Humeny A. MALDI-TOF-MS analysis of protein and DNA. Neurosci-

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entist 2001;7:6 –12.
stages, may be composed of untold numbers of combina- 11. Gygi SP, Aebersold R. Mass spectrometry and proteomics. Curr Opin Chem
tions of slight but significant shifts in protein–protein Biol 2000;4:489 –94.
interactions, protein folding, and protein abundances that 12. Adam BL, Vlahou A, Semmes OJ, Wright GL Jr. Proteomic approaches to
biomarker discovery in prostate and bladder cancers. Proteomics 2001;1:
are reflected in mass spectrometry-based protein profiles. 1264 –70.
Mass spectrometry platforms, already capable of re- 13. Carter D, Douglass JF, Cornellison CD, Retter MW, Johnson JC, Bennington
porting tens of thousands of events in less than a few AA, et al. Purification and characterization of the mammaglobin/lipophilin B
complex, a promising diagnostic marker for breast cancer. Biochemistry
minutes from a microliter of blood, are advancing rapidly 2002;41:6714 –22.
in speed, throughput, sensitivity, and “on-the-fly” protein 14. Rosty C, Christa L, Kuzdzal S, Baldwin WM, Zahurak ML, Carnot F, et al.
Identification of hepatocarcinoma-intestine-pancreas/pancreatitis-associ-
identification. Semiquantitative MSI profiling, as de- ated protein I as a biomarker for pancreatic ductal adenocarcinoma by
scribed in this issue, represents an additional new and protein biochip technology. Cancer Res 2002;62:1868 –75.
exciting component of the repertoire of mass spectrome- 15. Petricoin EF III, Ardekani AM, Hitt BA, Levine P, Fusaro VA, Steinberg S, et al.
Use of proteomic patterns in serum to identify ovarian cancer. Lancet
try’s diagnostic potential. 2002;359:572–7.
The coupling of advances in mass spectrometry with 16. Petricoin EF III, Mills GB, Kohn ES, Liotta L. Proteomic patterns in serum and
adaptive and vigilant bioinformatic pattern recognition identification of ovarian cancer [Reply]. Lancet 2002;360:170 –1.
17. Zhang LJ, Rosenzweig J, Wang YY, Chan DW. Proteomics and bioinformatics
tools may dramatically change how disease is detected approaches for identification of serum biomarkers to detect breast cancer.
and monitored. The result will be a rich source of infor- Clin Chem 2002;48:1296 –304.
mation to aid the clinician in patient management. On the 18. 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
basis of these nonlinear technologic advances, the clinical Cancer Inst 2002;94:1576 – 8.
diagnostic landscape is now shifting dramatically. Like it 19. Adam B-L, Qu Y, David JW, Ward MD, Clements MA, Cazares LH. Serum
protein fingerprinting coupled with a pattern-matching algorithm distin-
or not, we may be moving beyond existing immunoassay- guishes prostate cancer from benign prostate hyperplasia and healthy men.
based (for proteins) and electrophoretic (nucleic acid) Cancer Res 2002;62:3609 –14.
approaches. Rapid, low-cost mass spectrometry-based 20. Clarke S. Tandem mass spectrometry: the tool of choice for diagnosing
inborn errors of metabolism? Br J Biomed Sci 2002;59:42– 6.
alternatives with much higher clinical sensitivity and 21. Correlogic Systems. Correlogic Systems licenses ovarian cancer diagnostic
specificity for the detection and monitoring of disease test to Quest Diagnostics and LabCorp [Press Release]. http://www.corre-
may eventually dominate clinical diagnostics. The utility logic.com/questlabcorp_final.htm (accessed January 2003).
and validity of this vision will be answered over the next
several months to few years. Clinical trials for these Emanuel F. Petricoin1*
diagnostic tests are ongoing for early detection of cancer, Lance A. Liotta2
individualization of therapy, and monitoring of relapse 1
and drug-induced toxicity. As a demonstration of the NCI/FDA Clinical Proteomics Program
commercial interest in the expansion of mass spectrome- Office of the Director
try-based diagnostics (20 ), large reference laboratories Center for Biologics Evaluation and Research
have begun serious evaluation of the eventual implemen- Food and Drug Administration
tation of proteomic pattern diagnostics in their routine Bethesda, MD 20892
practice (21 ). 2
NCI/FDA Clinical Proteomics Program
References
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1. Coile RC Jr. The innovator’s dilemma: disruptive technologies. Russ Coiles Center for Cancer Research
Health Trends 2000;12:2– 4. National Cancer Institute
2. Christensen CM, Bohmer R, Kenagy J. Will disruptive innovations cure health Bethesda, MD 20892
care? Harv Bus Rev 2000;78:102–12,199.
3. Petricoin EF, Zoon KC, Kohn EC, Barrett JC, Liotta LA. Clinical proteomics:
translating benchside promise into bedside reality. Nat Rev Drug Discov
2002;1:683–95. *Author for correspondence.