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OtherLetters to the Editor

Validation of Breast Cancer Biomarkers Identified by Mass Spectrometry

Eleftherios P. Diamandis
DOI: 10.1373/clinchem.2005.064972 Published April 2006
Eleftherios P. Diamandis
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To the Editor:

Li et al. (1) should be congratulated for a valiant effort to validate 3 previously identified serum breast cancer biomarkers by surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS).

Because there is considerable controversy on the value of this technology for cancer diagnostics (2)(3)(4)(5)(6)(7)(8)(9)(10)(11), it is important to comment on validation studies aiming to reproduce previously published data. Among 3 previously reported biomarkers, BC1, BC2, and BC3, one of these (BC1) was not confirmed, as it was previously shown to be decreased in breast cancer, whereas in the validation study by Li et al. (1), it was increased.

The other 2 candidate biomarkers, BC2 and BC3, were positively identified, by tandem MS, as complement C3a lacking its C-terminal arginine (C3adesArg). BC2 was also identified as a truncated form of C3adesArg.

In my opinion, the data presented in Fig. 4 of the article by Li et al. (1), showing the relative intensities of BC2 and BC3 in various groups of patients, are rather disappointing. For BC2, there is no difference between patients with benign breast diseases and patients with invasive carcinomas, although an increase was seen in ductal carcinoma in situ (DCIS). For BC3, there was no difference among patients with benign disease, DCIS, or invasive carcinomas.

The remaining question concerns the possible value of complement C3adesArg and its fragment as candidate breast cancer biomarkers. The data provided by the authors (1) confirm my previous predictions that SELDI-TOF–identified biomarkers represent high-abundance proteins (in this case, C3, present in serum at concentrations of ∼1.2 g/L) that are produced mostly by the liver (3)(4)(5)(6). The proteolytic processing of peptides in the circulation by amino- and carboxypeptidases is well known, and it should not be surprising that the identified molecules represent modified and/or truncated forms of C3a.

I have previously speculated that a large number of SELDI-TOF–identified candidate biomarkers are acute-phase reactants (3)(4)(5)(6). C3, in accordance with my previous predictions, is also an acute-phase reactant whose serum concentration is increased or decreased in a wide variety of clinical conditions (12).

I conclude that the positive identification of previously described candidate serum biomarkers, BC2 and BC3, confirms my previous predictions that these are high-abundance proteins produced by the liver and that they represent nonspecific biomarkers of acute-phase reaction. Their performance as breast cancer biomarkers, as assessed by SELDI immunoassay, is not impressive and likely of questionable clinical value.

  • © 2006 The American Association for Clinical Chemistry

References

  1. ↵
    Li J, Orlandi R, White CN, Rosenzweig J, Zhao J, Seregni E, et al. Independent validation of candidate breast cancer serum biomarkers identified by mass spectrometry. Clin Chem 2005;51:2229-2235.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    Simpkins F, Czechowicz JA, Liotta L, Kohn EC. SELDI-TOF mass spectrometry for cancer biomarker discovery and serum proteomic diagnostics. Pharmacogenomics 2005;6:647-653.
    OpenUrlCrossRefPubMed Order article via Infotrieve
  3. ↵
    Diamandis EP. Proteomic patterns in biological fluids: do they represent the future of cancer diagnostics?. Clin Chem 2003;49:1272-1278.
    OpenUrlFREE Full Text
  4. ↵
    Diamandis EP. Analysis of serum proteomic patterns for early cancer diagnosis: drawing attention to potential problems. J Natl Cancer Inst 2004;96:353-356.
    OpenUrlFREE Full Text
  5. ↵
    Diamandis EP. Mass spectrometry as a diagnostic and a cancer biomarker discovery tool: opportunities and potential limitations. Mol Cell Proteomics 2004;3:367-368.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    Diamandis EP, van der Merwe D-E. Plasma protein profiling by mass spectrometry for cancer diagnosis: opportunities and limitations. Clin Cancer Res 2005;11:963-965.
    OpenUrlFREE Full Text
  7. ↵
    Master SR. Diagnostic proteomics. Back to basics?. Clin Chem 2005;51:1333-1334.
    OpenUrlFREE Full Text
  8. ↵
    Karsan A, Eigl BJ, Flibotte S, Gelmon K, Switzer P, Hassell P, et al. Analytical and preanalytical biases in serum proteomic pattern analysis for breast cancer diagnosis. Clin Chem 2005;51:1525-1528.
    OpenUrlFREE Full Text
  9. ↵
    Banks RE, Stanley AJ, Cairns DA, Barrett JH, Clarke P, Thompson D, et al. Influences of blood sample processing on low-molecular-weight proteome identified by surface-enhanced laser desorption/ionization mass spectrometry. Clin Chem 2005;51:1637-1649.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Ransohoff DF. Bias as a threat to the validity of cancer molecular-marker research. Nat Rev Cancer 2005;5:142-149.
    OpenUrlCrossRefPubMed Order article via Infotrieve
  11. ↵
    Baggerly KA, Morris JS, Edmonson SR, Coombes KR. Signal in noise: evaluating reported reproducibility of serum proteomic tests for ovarian cancer. J Natl Cancer Inst 2005;97:307-309.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Johnson AM. Amino acids, peptides, and proteins. Burtis CA Ashwood ER Bruns DE eds. Tietz textbook of clinical chemistry and molecular diagnostics 2005:533-595 Elsevier New York. .
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Clinical Chemistry: 52 (4)
Vol. 52, Issue 4
April 2006
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Validation of Breast Cancer Biomarkers Identified by Mass Spectrometry
Eleftherios P. Diamandis
Clinical Chemistry Apr 2006, 52 (4) 771-772; DOI: 10.1373/clinchem.2005.064972
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Validation of Breast Cancer Biomarkers Identified by Mass Spectrometry
Eleftherios P. Diamandis
Clinical Chemistry Apr 2006, 52 (4) 771-772; DOI: 10.1373/clinchem.2005.064972

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