A list of candidate cancer biomarkers for targeted proteomics

Abstract

We have compiled from literature and other sources a list of 1261 proteins believed to be differentially expressed in human cancer. These proteins, only some of which have been detected in plasma to date, represent a population of candidate plasma biomarkers that could be useful in early cancer detection and monitoring given sufficiently sensitive specific assays. We have begun to prioritize these markers for future validation by frequency of literature citations, both total and as a function of time. The candidates include proteins involved in oncogenesis, angiogenesis, development, differentiation, proliferation, apoptosis, hematopoiesis, immune and hormonal responses, cell signaling, nucleotide function, hydrolysis, cellular homing, cell cycle and structure, the acute phase response and hormonal control. Many have been detected in studies of tissue or nuclear components; nevertheless we hypothesize that most if not all should be present in plasma at some level. Of the 1261 candidates only 9 have been approved as "tumor associated antigens" by the FDA. We propose that systematic collection and large-scale validation of candidate biomarkers would fill the gap currently existing between basic research and clinical use of advanced diagnostics.

Keywords: biomarkers; cancer; targeted proteomics; validation.

Figure 1

Biomarker Citation Frequency. Citation Frequency for each protein was determined using the PubMed query [“protein name” AND human AND cancer AND diagnostic]. Proteins were then histogrammed in bins of 10, 100 and 1000 citations (for frequencies of n<100, 1001000, respectively) and each bin’s count normalized through division by bin size (eg the count of proteins falling in the 11–20 citations bin was divided by 10).

Figure 2

Proteins with greater than 1000 citations in Fig 1. White bars indicate non plasma proteins not used clinically, light gray bars indicate clinically used proteins not yet detected in plasma, dark gray bars indicate plasma proteins not used clinically and black bars indicate plasma proteins used clinically. CEA = Carcinoembryonic Antigen, PSA = Prostate Specific Antigen, ER alpha = Estrogen Receptor alpha, LH = Luteinizing Hormone, PR = Progesterone Receptor, PCNA = Proliferating Cell Nuclear Antigen, FSH = Follicle-stimulating Hormone, NSE = Neuron-specific enolase, PH=Parathyroid Hormone.

Figure 3

Proteins with greater than 500 but less than 1000 citations in Fig. 1. White bars indicate non-plasma proteins not used clinically, dark gray bars indicate plasma proteins not used clinically and black bars indicate plasma proteins used clinically. Beta-2-MG = Beta–2-microglobulin, IFN-gamma = IFN-gamma, CRP = C reactive protein, CGA = Chromogranin A, EPN = Erythropoietin, VWF=Von Willebrand Factor.

Figure 4

Proteins of “recent” interest (more than 50% of Fig. 1., citations occurring in 2004). White bars indicate non-plasma proteins not used clinically, dark gray bars indicate plasma proteins not used clinically. MG B = Mammaglobin B, HG = Haptoglobin 1, S-gamma = Synuclein-gamma, NESP-55 = Neuroendocrine secretory protein-55, CDK-6 = Cyclin-dependent kinase 6, 17betaHD1 = 17 beta-Hydroxys-teroid dehydrogenase type 1.

Figure 5

Evolution of Marker Interest. The number of times a marker is cited in a particular year divided by the total number of cancer citations for that year. Solid gray stars designate when the FDA approved CEA, PSA and alpha-fetoprotein. CEA = Carcinoembryonic Antigen, PSA = Prostate Specific Antigen, PDGRFR = Platelet-derived Growth Factor Receptor alpha.

Figure 6

Distribution of Normal Plasma Concentrations for Plasma Cancer Biomarkers. The number of plasma concentrations falling within a given log of pg/ml were normalized to percent of total and then were histogrammed in log bins. The concentrations of the 211 cancer biomarkers detected in plasma are represented by the solid line, the concentrations of the unselected plasma proteins by the dashed line, and the concentration of cardiac biomarkers by the dotted line.

Figure 7

Distribution by Biological Process. Genome Ontology categories for A) Cancer biomarker proteins, B) Overall human proteome (genome data).

Figure 8

Distribution by Cellular Component. Genome Ontology categories for A) Cancer biomarker proteins, B) Overall human proteome (genome data).

Figure 9

Distribution by Molecular function. Genome Ontology categories for A) Cancer biomarker proteins, B) Overall human proteome (genome data).