Plasma Proteomic Signatures

Perturbations of the proteome that arise as either a cause or consequence of disease manifest as particular patterns of proteins in the blood. This patterning concept has been the basis for recent efforts to discover proteomic "signatures" in serum. Mass spectrometers can rapidly generate well-defined sets of proteomic peaks from a sample across a broad range of mass/charge. A growing controversy is whether such "protein signatures"

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Membrane " 19%

Fig. 6. Protein composition of human plasma. (From ref. 6.)

Membrane " 19%

Fig. 6. Protein composition of human plasma. (From ref. 6.)

can be used to distinguish accurately disease states from normal. A significant time advantage of direct profile comparisons derives from skipping the far more laborious task of unambiguously identifying the proteins that underlie the peaks. Thus, rapid screening of patient samples is possible. By virtue oftheir inclusion ofmultiple proteins, such signatures may have increased diagnostic sensitivity over single protein biomarkers. Most serum profiles to date have been performed in the context of various cancers, including those of the ovary, breast, prostate, and liver. In one highly publicized effort, it was demonstrated that MS coupled with an artificial intelligence algorithm could distinguish ovarian cancer from normal controls with an unprecedented 100% sensitivity and 95% specificity (8).

Using a pattern of peaks to diagnose disease without knowing the represented proteins, however, raises some concerns. One issue is that of reproducibility. Because most mass spectrometers were not designed as clinical tools, it is hard to generate consistent results from machine to machine or from operator to operator. Some contend that the patterns are mostly "noise" and do not discriminate biologically meaningful information. Independent reanalysis of the cancer proteomics data has cast some doubt regarding bias and validity of the data. Without unequivocal protein identifications, one cannot independently confirm findings with complementary technologies such as enzyme-linked immunosorbent assay. Others contend that the peaks profiled by the methodologies used to date only represent the most abundant plasma protein constituents. Such proteins are unlikely to have been released or induced into circulation by very small tumors or their microenvironments. Supporters argue that even when noted peaks are derived from abundant proteins, or represent unusual modifications of abundant proteins such as Ig or albumin, their role as biomarkers is not diminished. The most important consequence of not unequivocally identifying proteins, however, is that little insight is gained into the biology, either to understand disease pathways through basic cellular mechanisms or as a check on the biological consistency and reasonableness ofthe data. Thus, despite the impressiveness of the results, explaining the data requires one to invoke novel biological hypotheses. Blinded prospective studies must ultimately be organized to better address the controversy.

Researchers have begun to apply protein profiling to CVD, specifically investigating serum signatures of MI. One team of researchers has attempted to identify patterns in the serum of patients with MI (9). These researchers a diagnostic series of peptide peaks differentially expressed in diseased sera. Ultimately, several peaks were found to relate to complement and fibrinogen products. The researchers acknowledged that the reported patterns were influenced by storage and handling conditions, thus underscoring the importance of sample quality in proteomics studies. Again, prospective validation of such findings in new epidemiological cohorts is critical.

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