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Proteomic and Genomic Technologies for Biomarker Discovery Where Are the Biomarkers? Vathany Kulasingam and Eleftherios P

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Proteomic and Genomic Technologies for Biomarker Discovery Where Are the Biomarkers? Vathany Kulasingam and Eleftherios P 02_Diamandis_Editorial_1.qxd 11/21/06 3:06 PM Page 5 Clinical Proteomics Copyright © 2006 Humana Press Inc. All rights of any nature whatsoever are reserved. ISSN 1542-6416/06/02:05–12/$30.00 (Online) Editorial Proteomic and Genomic Technologies for Biomarker Discovery Where Are the Biomarkers? Vathany Kulasingam and Eleftherios P. Diamandis* Laboratory Medicine and Pathobiology, University of Toronto,Toronto, ON, Canada and Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave.,Toronto, ON M5G 1X5, Canada Introduction cancer, as it is a model disease for studying such applications. Recently, we have witnessed the emer- gence of the “-omics” era with proteomics, Current Cancer Biomarkers peptidomics, degradomics, metabolomics, fractionomics, transcriptomics, interactomics, Despite tremendous progress in our under- and so forth. However, the only “-omics” standing of the molecular basis of many dis- other than genomics to become a “buzz- eases, cancer continues to be a major cause of word” is proteomics, a term used for studying morbidity and mortality among men and the proteome of an organism. With the com- women. There is convincing evidence that early pletion of the Human Genome Project, opti- detection of cancer can lead to better patient mistic views were expressed that novel outcomes through early administration of disease-specific biomarkers will be discov- therapy (1). Also, better clinical outcomes can ered through various high-throughput tech- be achieved with individualized treatments, niques, such as microarrays and mass which are more effective in subgroups of spectrometry (MS). Did the current technolo- patients, rather than in the total patient popu- gies deliver the goods? In the following, we lation. One of the best ways to diagnose cancer discuss briefly the current status and future early, or to predict therapeutic responses, is by of proteomics and genomics with respect to using serum or tissue biomarkers. *Author to whom all correspondence and reprint requests should be addressed: Eleftherios P. Diamandis, Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada and Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 600 University Ave., Toronto, ON M5G 1X5, Canada. E-mail: [email protected]. 5 02_Diamandis_Editorial_1.qxd 11/21/06 3:06 PM Page 6 6 ____________________________________________________________________ Kulasingam and Diamandis Currently, a number of cancer biomarkers proteomics and genomics community to dis- are used clinically, including prostate-specific cover novel biomarkers. antigen (PSA; for prostate cancer), carcinoem- Some Proteomic and Genomic bryonic antigen (CEA; for colon, lung, and breast cancer), the carbohydrate antigens (CA) Approaches to Biomarker 125 (for ovarian cancer), CA 15.3 (for breast Discovery cancer), CA 19.9 (for gastrointestinal cancer), A number of different proteomic- and α-fetoprotein (AFP; for liver and testicular genomic-based approaches have been utilized cancer), and human choriogonadotropin (hCG; to date to discover disease-specific biomarkers. for testicular and gestational cancers). All of Some of the approaches and strategies are these markers, despite being generally not suit- briefly described here along with an example able for population screening (because of low of how these methodologies were applied to diagnostic sensitivity and specificity), play a aid in biomarker discovery or to develop pat- major role in aiding diagnosis and for moni- terns for early diagnosis. toring patients during therapy. Unfortunately, these cancer biomarkers have proven to be Two-Dimensional Gel Electrophoresis ineffective in detecting the early stages of dis- and Mass Spectrometry ease and many suffer from low positive pre- Two-dimensional polyacrylamide gel elec- dictive values. trophoresis, known traditionally as the gold Renewed Interest in Cancer standard, discovery-based tool for proteo- mics, aims to resolve and visualize protein Biomarkers spots that are differentially expressed in Historically, every era of cancer biomarker healthy vs diseased samples. The spots can discovery was associated with the emergence be excised from the gel, digested, and sub- of a powerful analytical technology. For sequently identified via MS. Using this example, CEA was discovered in the 1960s methodology, Celis et al. (3) developed a mainly as a result of the introduction of novel comprehensive database for bladder cancer and relatively sensitive immunological tech- profiles of both transitional and squamous niques (such as radial immuno-diffusion), cell carcinomas. Furthermore, Kageyama et al. which allowed for the detection of the anti- (4) used a differential display method of gen in cancer tissues with high specificity bladder cancer vs healthy urothelial tissue and reasonable sensitivity. CA 125 and other and MS to identify proteins, which are CAs were developed, in the late 1970s, increased in cancer tissues. Calreticulin, a because of the establishment of the mono- potential tumor marker, was identified in clonal antibody technology. Most of these this study as it was found in urine of tumor markers were discovered by using cell patients with bladder cancer. The authors lines or tumor extracts as immunogens and confirmed their data with Western blot anal- then selecting specific hybridoma clones that ysis, immunoprecipitation, and immunohis- recognized these tumor antigens (2). With the tochemistry. They reported a sensitivity of completion of the Human Genome Project 73% and a specificity of 86%. However, a and the introduction of technologies that caveat to this technology is that the identi- enabled simultaneous examination of thou- fied proteins are usually of high abundance sands of proteins and genes at any given and the method is labor intensive. Similar time, such as MS and protein and DNA strategies have been used by many other arrays, a renewed interest was taken by the groups. Clinical Proteomics ________________________________________________________________ Volume 2, 2006 02_Diamandis_Editorial_1.qxd 11/21/06 3:06 PM Page 7 Editorial ___________________________________________________________________________________ 7 Protein Arrays noncancer. This pattern was used to classify Another area of proteomic research that is 116 blinded serum samples. The results were gaining popularity is the use of protein arrays exceptional with a sensitivity of 100% at 95% to identify novel biomarkers. Chinnaiyan and specificity. These numbers are far superior to colleagues recently published data suggesting the sensitivities and specificities obtained with that autoantibody signatures may improve the current serologic cancer biomarkers. early detection of prostate cancer (5). Using a MS-Imaging (MALDI-MS) combination of phage-display technology and protein microarrays, they identified new Another proteomic pattern analysis approach autoantibody-binding peptides derived from involves the use of matrix-assisted laser des- prostate cancer tissue. Serum samples from 119 orption/ionization (MALDI)-MS on small patients with prostate cancer and 138 control amounts of fresh frozen tissue sections. In a patients were analyzed using this methodol- recent application of this methodology, termed ogy. Their results were impressive. A 22-phage MS imaging, pioneered by Caprioli and col- peptide detector had 88% specificity and 82% leagues (7), the authors profiled the protein sensitivity in discriminating between the two expression of surgically resected lung tumor groups. This panel of peptides seemed to per- tissues (8). To detect proteomic patterns in form better than PSA in distinguishing lung tumors, the protein expression profiles of between prostate cancer and the control group. 50 tissue samples (42 lung tumors and 8 normal lung samples) in a training cohort was Proteomic Pattern Analysis (SELDI-TOF) assessed. Mass spectra were obtained directly The ability to identify diseases through pro- from 1-mm regions of single frozen tissue sec- teomic patterns in biological fluids appeared tions. More than 1600 distinct protein species to be a new paradigm shift in the use of MS- were observed, of which 82 discriminating MS based methodologies. This approach attracted signals were selected. A class-prediction model considerable attention over the past few years. was built and it was able to correctly classify Developed by Petricoin, Liotta, and colleagues, all 42 lung tumors and the 8 normal samples. this potentially revolutionary methodology This model was further validated in an inde- involves the use of a minute amount of unfrac- pendent blinded test cohort yielding a phe- tionated serum sample added to a “protein- nomenal result of perfect classification of the chip,” which is subsequently analyzed by samples. surface-enhanced laser desorption/ionization time-of-flight (SELDI-TOF) spectrometry to Quantitative Proteomics generate a proteomic signature of the serum. Quantitative proteomics aims to measure These patterns reflect part of the blood pro- quantitatively the relative or absolute abun- teome, without knowledge of the actual iden- dance of proteins across samples. The emer- tity of the proteins that make up the proteome. gence of experimental protocols, such as The potential of proteomic pattern analysis isotope-coded affinity tags (ICAT), iTRAQ™, was first demonstrated in the diagnosis of stable isotope labeling by amino acids in cell ovarian cancer (6). In this study, a preliminary culture
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