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Mass Spectrometry
- Mass Spectrometry as a Diagnostic and a Cancer Biomarker Discovery Tool


Mass spectrometry has been used as a diagnostic tool in clinical laboratories for many decades. This technology has been coupled with gas chromatography (GC/MS) 1 and has been used with success for the identification and quantification of relatively small molecules (with molecular mass could be highly informative in newborn screening programs (13), toxicological and forensic applications (14), for delineating various types of inborn errors of metabolism (15), for detecting doping of athletes (16), etc. Over the last 15 years, we have seen a resurgence of this technology for studying larger molecules such as nucleic acids and proteins. These new applications became possible mainly due to the development of novel methodologies to effectively volatize and ionize proteins and nucleic acids, by using various chemicals (matrices) and lasers (e.g. matrix-assisted laser desorption/ionization, MALDI) or electrospray ionization (ESI). The ability to measure with high accuracy mass-to-charge ratio, providing spectra of very high resolution, and the development of tandem mass spectrometry (MS/MS) to obtain de novo protein sequence information has further enhanced the applications of this technology in proteomics. Coupling of mass spectrometers to liquid chromatrography (LC/MS) further expanded the discriminatory power of the method. Mass spectrometry is now one of the most powerful proteomic tools (17). Even more spectacular advances in mass spectrometry should be expected, with further improvements in resolution and detectability. With this in mind, it is not surprising that many scientists have decided to use mass spectrometry either as a diagnostic tool or as a cancer or other disease biomarker discovery platform (212).

I will need to emphasize at this point that the critical discussion to follow is not directed against either mass spectrometry or to the field of proteomics in general. In fact, these methods and fields of investigation, used appropriately, may indeed succeed in discovering new diagnostic modalities for cancer and other diseases, as well as contribute to the better understanding of the pathogenesis of such diseases. The Human Proteome Organization (HUPO, www.hupo.org) is focusing on the identification of large numbers of proteins in complex mixtures, including serum and other biological fluids (17). It is expected that these efforts will finally lead to the identification of new potential biomarkers for cancer and other diseases. HUPO also intends to standardize the methodology so that the results obtained with these techniques are robust and reproducible among laboratories.

Most of the discussion below will focus on one proteomic platform used extensively in diagnostics, known as surface-enhanced laser desorption/ionization-time-of-flight (SELDI-TOF) mass spectrometry. This technique is based on the pretreatment of a biological fluid or tissue extract with various proteomic chips, performing protein extractions based on hydrophobic, ion-exchange, metal binding, or other interactions. The bound proteins are then subjected to mass spectrometric analysis. The derived information can be used for either diagnosis or for identifying potential biomarkers that could then be further validated with alternative technologies. These issues will be discussed in detail below.

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