Classification of cancer types by measuring variants of host response proteins using SELDI serum assays

Abstract

Protein expression profiling has been increasingly used to discover and characterize biomarkers that can be used for diagnostic, prognostic or therapeutic purposes. Most proteomic studies published to date have identified relatively abundant host response proteins as candidate biomarkers, which are often dismissed because of an apparent lack of specificity. We demonstrate that 2 host response proteins previously identified as candidate markers for early stage ovarian cancer, transthyretin and inter-alpha trypsin inhibitor heavy chain 4 (ITIH4), are posttranslationally modified. These modifications include proteolytic truncation, cysteinylation and glutathionylation. Assays using Surface Enhanced Laser Desorption/Ionization Time of Flight Mass Spectrometry (SELDI-TOF-MS) may provide a means to confer specificity to these proteins because of their ability to detect and quantitate multiple posttranslationally modified forms of these proteins in a single assay. Quantitative measurements of these modifications using chromatographic and antibody-based ProteinChip1 array assays reveal that these posttranslational modifications occur to different extents in different cancers and that multivariate analysis permits the derivation of algorithms to improve the classification of these cancers. We have termed this process host response protein amplification cascade (HRPAC), since the process of synthesis, posttranslational modification and metabolism of host response proteins amplifies the signal of potentially low-abundant biologically active disease markers such as enzymes. ' 2005 Wiley-Liss, Inc.

Identification of disease- and therapy-associated proteome changes in the sera of patients with myelodysplastic syndromes and del(5q)

“…In addition to m/z 2791, a group of peaks at m/z 3274, m/z 3956, m/z 3972, m/z 4282 and m/z 4298 derived from inter-a-trypsin inhibitor heavy chain H4 were also significantly increased in the diseased samples. Quantitative alteration of the fragments of inter-a trypsin inhibitor, heavy chain H4 was previously found to be associated with various cancer diseases, [22][23][24] indicating that the alteration of these species is not specific to MDS. Inter-a trypsin inhibitor, heavy chain H4 has been shown to be a positive acute phase protein in human and other animals, [25][26][27] thus the increase of these species might be associated with the inflammatory processes ongoing in MDS.…”

Postoperative serum proteomic profiles may predict metastatic relapse in high-risk primary breast cancer patients receiving adjuvant chemotherapy

“…Among this unfavorable group classically defined by lymph node invasion and/or large tumor size, young age, high SBR grade, negative hormonal receptivity (NIH, 2001;Goldhirsch et al, 2003), a more accurate identification of patients that will be ultimately cured with conventional adjuvant chemotherapy or that will experience metastatic relapse is critical. Such an a priori knowledge could confer a higher probability of cure with currently available therapeutic strategies to certain patients, while redirecting others toward more innovative and/or aggressive strategies.…”

“…Prognostic factors currently used by clinicians for decisions of adjuvant chemotherapy have been reported during the consensus conferences of National Institute Health (NIH) and St-Gallen (NIH, 2001;Goldhirsch et al, 2003). They include clinical (ageo40 years) and pathological (tumor size >10-20 mm, lymph node invasion, Scarff-BloomRichardson (SBR) grade II-III, no hormonal receptivity) parameters.…”

“…As blood circulates through all areas of the body, it might be modified either qualitatively or quantitatively by virtually every tissue encountered. Consequently, serum may be an appropriate surrogate tissue to investigate since it may share the fingerprint of various physiologic or pathologic processes involving cancer tissue and/or host response (Fung et al, 2005). Coupled to appropriate bioinformatic tools, SELDI-TOF MS was recently shown as a very promising method for probing serum to identify protein patterns and/or biomarkers related to various stages and types of solid tumors (Adam et al, 2002a;Petricoin et al, 2002a, b;Koopmann et al, 2004;Wadsworth et al, 2004;Zhang et al, 2004), which could serve as early diagnostic markers.…”

Plasma and tissue proteomic prognostic factors of response in primary breast cancer patients receiving neoadjuvant chemotherapy

“…Surface-enhanced laser desorption/ionization-time of flight (SELDI-TOF) mass spectrometry (MS) coupled with appropriate bio-informatic tools have been used to identify protein patterns related to various stages and types of solid tumors and serum (5)(6)(7)(8)(9)(10)(11)(12). This technology combines chromatographic fractionation of the proteome using protein biochips and TOF MS analysis that can be applied to various clinical samples, such as serum and tissue (13); it allows relatively high-throughput protein analysis of complex biological samples, with limited preprocessing steps.…”