Classification of cancer types by measuring variants of host response proteins using SELDI serum assays.
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 ProteinChip 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.
Fung
Eric T
ET
Ciphergen Biosystems, Fremont, CA 94555, USA. efung@ciphergen.com
Yip
Tai-Tung
TT
Lomas
Lee
L
Wang
Zheng
Z
Yip
Christine
C
Meng
Xiao-Ying
XY
Lin
Shanhua
S
Zhang
Fujun
F
Zhang
Zhen
Z
Chan
Daniel W
DW
Weinberger
Scot R
SR
D000465:Algorithms; D000510:Alpha-Globulins / Q000032:analysis / Q000096:biosynthesis; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000145:classification* / Q000175:diagnosis* / Q000276:immunology; D003110:Colonic Neoplasms / Q000145:classification* / Q000175:diagnosis* / Q000276:immunology; D005260:Female; D006801:Humans; D007249:Inflammation; D008297:Male; D010051:Ovarian Neoplasms / Q000145:classification* / Q000175:diagnosis* / Q000276:immunology; D011228:Prealbumin / Q000032:analysis / Q000096:biosynthesis; D011471:Prostatic Neoplasms / Q000145:classification* / Q000175:diagnosis* / Q000276:immunology; D040081:Protein Array Analysis; D011499:Protein Processing, Post-Translational; D040901:Proteomics; D012680:Sensitivity and Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D000510:Alpha-Globulins; D014408:Biomarkers, Tumor; D011228:Prealbumin; C011877:inter-alpha-inhibitor