Affiliations of author: E. P. Diamandis, Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and the Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada.
Correspondence to: Eleftherios P. Diamandis, M.D., Ph.D., F.R.C.P.C., Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario M5G 1X5, Canada (e-mail: ediamandis{at}mtsinai.on.ca).
Petricoin et al. (1) proposed that assessment of serum proteomic patterns with mass spectrometry and combination of these patterns with a bioinformatic algorithm can detect prostate cancer with approximately 95% sensitivity and 70%80% specificity. These figures seem favorable when compared with common biochemical testing for prostate cancer, which currently includes analysis of total prostate-specific antigen (PSA) and percent free PSA in serum. Similar approaches have been proposed by the same group for the diagnosis of ovarian and other cancers (2).
The authors speculate that the discriminatory proteomic patterns originate from proteins (including cytokines, chemokines, metabolites, or enzymatic cleavage products) released by the prostate or its microenvironment during blood percolation through the organ. However, a limitation of this technology, also discussed elsewhere (3), is that the authors offer no evidence in regard to the identity of their seven most discriminatory molecules. In a previous publication (4), the authors contend that the identity of these proteins is not important in the context of their method. However, the identity of such proteins, as well as their relative concentrations in serum, is of paramount importance for understanding why they offer discriminatory power for detecting prostate cancer and how they originated in the circulation. For example, to derive their algorithm, Petricoin et al. (1) used serum samples from patients with biopsy-proven prostate cancer and total PSA levels of more than 4 ng/mL and from patients with no evidence of disease and total PSA levels of less than 1 ng/mL. It would have been interesting to know whether the authors method identified this internal control and highly discriminating molecule (i.e., PSA) as one of the discriminatory proteins in serum. Such a finding would confirm that their method is sensitive enough to detect proteins at a concentration level of 1 ng/mL or higher. Their method of extracting serum prior to analysis (i.e., by hydrophobic interaction with a C16 column), which is not specific for any molecule, would favor the isolation of highly abundant serum proteins and the loss of low-abundance proteins. Furthermore, the current sensitivity of mass spectrometry would preclude identification of molecules present in serum at nanogram-per-milliliter levels, unless shown otherwise by the authors. Because PSA is present in the prostate and seminal plasma at milligram-per-milliliter levels, but only at 106-fold lower levels in serum, it would seem unlikely that prostate-derived proteins would be detected efficiently in serum by the authors method. This information would most likely lead to the conclusion that the discriminatory proteins identified in the serum of these patients are unlikely to come from prostate tissue. Instead, these proteins are probably epiphenomena of cancer, represented by highly abundant nonprostatic proteinsthat is, they could be acute phase reactants. Such epiphenomena could lead to errors when used for diagnosis, especially in patients with diverse abnormalities, such as malnutrition, diabetes, inflammation, and infections.
Given the implications of the reported findings by Petricoin et al. (1), it will be important to identify the nature of the discriminatory proteins, their concentration in the circulation, and their tissue(s) of origin. Such identification would allow for a better understanding of their differential expression and association with prostate cancer.
REFERENCES
1 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.
2 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 2002;359:5727.[CrossRef][Medline]
3 Diamandis EP. Proteomic patterns in serum and identification of ovarian cancer. Lancet 2002;360:170.
4 Petricoin EF III, Mills GB, Kohn ES, Liotta L. Proteomic patterns in serum and identification of ovarian cancer. Lancet 2002;360:1701.
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