Omics-Based Molecular Target and Biomarker Identification

  • Zhang-Zhi HuEmail author
  • Hongzhan Huang
  • Cathy H. Wu
  • Mira Jung
  • Anatoly Dritschilo
  • Anna T. Riegel
  • Anton Wellstein
Part of the Methods in Molecular Biology book series (MIMB, volume 719)


Genomic, proteomic, and other omic-based approaches are now broadly used in biomedical research to facilitate the understanding of disease mechanisms and identification of molecular targets and biomarkers for therapeutic and diagnostic development. While the Omics technologies and bioinformatics tools for analyzing Omics data are rapidly advancing, the functional analysis and interpretation of the data remain challenging due to the inherent nature of the generally long workflows of Omics experiments. We adopt a strategy that emphasizes the use of curated knowledge resources coupled with expert-guided examination and interpretation of Omics data for the selection of potential molecular targets. We describe a downstream workflow and procedures for functional analysis that focus on biological pathways, from which molecular targets can be derived and proposed for experimental validation.

Key words

Proteomics Genomics Bioinformatics Biological pathways Cell signaling Databases Molecular targets Biomarkers 



The work has been supported in part by Federal funds from the National Cancer Institute (NCI), National Institutes of Health (NIH), under Contract No. HHSN261200800001E (Z.Z.H.), by NCI grant P01CA074175 (A.D.), by NIH grant U01-HG02712 (C.W.), and by the Department of Defense Breast Cancer Research Program W81XWH-06-10590 Center of Excellence Grant (A.W., A.T.R.). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.


  1. 1.
    Ransohoff, D.F. (2003). Cancer. Developing molecular biomarkers for cancer Science 299, 1679–80.PubMedCrossRefGoogle Scholar
  2. 2.
    Riesterer, O., Milas, L., and Ang, K.K. (2007) Use of molecular biomarkers for predicting the response to radiotherapy with or without chemotherapy J Clin Oncol 25, 4075–83.PubMedCrossRefGoogle Scholar
  3. 3.
    Kim, Y.S., Maruvada, P., and Milner, J.A. (2008) Metabolomics in biomarker discovery: future uses for cancer prevention Future Oncol 4, 93–102.PubMedCrossRefGoogle Scholar
  4. 4.
    Tainsky, M.A. (2009) Genomic and proteomic biomarkers for cancer: a multitude of opportunities Biochim Biophys Acta 1796, 176–93.PubMedGoogle Scholar
  5. 5.
    Hanash, S. (2004) Integrated global profiling of cancer Nat Rev Cancer 4, 638–44.PubMedCrossRefGoogle Scholar
  6. 6.
    Souchelnytskyi, S. (2005) Proteomics of TGF-beta signaling and its impact on breast cancer Expert Rev Proteomics 2, 925–35.PubMedCrossRefGoogle Scholar
  7. 7.
    Walgren, J.L., and Thompson, D.C. (2004) Application of proteomic technologies in the drug development process Toxicol Lett 149, 377–85.PubMedCrossRefGoogle Scholar
  8. 8.
    Tugwood, J.D., Hollins, L.E., and Cockerill, M.J. (2003) Genomics and the search for novel biomarkers in toxicology Biomarkers 8, 79–92.PubMedCrossRefGoogle Scholar
  9. 9.
    Merrick, B.A., and Bruno, M.E. (2004) Genomic and proteomic profiling for biomarkers and signature profiles of toxicity Curr Opin Mol Ther 6, 600–7.PubMedGoogle Scholar
  10. 10.
    Sreekumar, A., Poisson, L.M., Rajendiran, T.M., Khan, A.P., Cao, Q., Yu, J., Laxman, B., Mehra, R., Lonigro, R.J., Li, Y., Nyati, M.K., Ahsan, A., Kalyana-Sundaram, S., Han, B., Cao, X., Byun, J., Omenn, G.S., Ghosh, D., Pennathur, S., Alexander, D.C., Berger, A., Shuster, J.R., Wei, J.T., Varambally, S., Beecher, C., and Chinnaiyan, A.M. (2009) Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression Nature 457, 910–4.PubMedCrossRefGoogle Scholar
  11. 11.
    Martens, J.W., Margossian, A.L., Schmitt, M., Foekens, J., and Harbeck, N. (2009) DNA methylation as a biomarker in breast cancer Future Oncol 5, 1245–56.PubMedCrossRefGoogle Scholar
  12. 12.
    Ruan, K., Fang, X., and Ouyang, G. (2009) MicroRNAs: novel regulators in the hallmarks of human cancer Cancer Lett 285, 116–26.PubMedCrossRefGoogle Scholar
  13. 13.
    Brooks, S.A. (2009) Strategies for analysis of the glycosylation of proteins: current status and future perspectives Mol Biotechnol 43, 76–88.PubMedCrossRefGoogle Scholar
  14. 14.
    Pang, J., Liu, W.P., Liu, X.P., Li, L.Y., Fang, Y.Q., Sun, Q.P., Liu, S.J., Li, M.T., Su, Z.L., and Gao, X. (2010) Profiling protein markers associated with lymph node metastasis in prostate cancer by DIGE-based proteomics analysis J Proteome Res 9(1), 216–26.PubMedCrossRefGoogle Scholar
  15. 15.
    Li, J., Zhao, J., Yu, X., Lange, J., Kuerer, H., Krishnamurthy, S., Schilling, E., Khan, S.A., Sukumar, S., and Chan, D.W. (2005) Identification of biomarkers for breast cancer in nipple aspiration and ductal lavage fluid Clin Cancer Res 11, 8312–20.PubMedCrossRefGoogle Scholar
  16. 16.
    Zhou, J., Trock, B., Tsangaris, T.N., Friedman, N.B., Shapiro, D., Brotzman, M., Chan-Li, Y., Chan, D.W., and Li, J. (2010) A unique proteolytic fragment of alpha1-antitrypsin is elevated in ductal fluid of breast cancer patient Breast Cancer Res Treat 123(1), 73–86.PubMedCrossRefGoogle Scholar
  17. 17.
    Yamamoto, Y., Kosaka, N., Tanaka, M., Koizumi, F., Kanai, Y., Mizutani, T., Murakami, Y., Kuroda, M., Miyajima, A., Kato, T., and Ochiya, T. (2009) MicroRNA-500 as a potential diagnostic marker for hepatocellular carcinoma Biomarkers 14, 529–38.PubMedCrossRefGoogle Scholar
  18. 18.
    Jones, S., Zhang, X., Parsons, D.W., Lin, J.C., Leary, R.J., Angenendt, P., Mankoo, P., Carter, H., Kamiyama, H., Jimeno, A., Hong, S.M., Fu, B., Lin, M.T., Calhoun, E.S., Kamiyama, M., Walter, K., Nikolskaya, T., Nikolsky, Y., Hartigan, J., Smith, D.R., Hidalgo, M., Leach, S.D., Klein, A.P., Jaffee, E.M., Goggins, M., Maitra, A., Iacobuzio-Donahue, C., Eshleman, J.R., Kern, S.E., Hruban, R.H., Karchin, R., Papadopoulos, N., Parmigiani, G., Vogelstein, B., Velculescu, V.E., and Kinzler, K.W. (2008) Core signaling pathways in human pancreatic cancers revealed by global genomic analyses Science 321, 1801–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Zhu, X., Gerstein, M., and Snyder, M. (2007) Getting connected: analysis and principles of biological networks Genes Dev 21, 1010–24.PubMedCrossRefGoogle Scholar
  20. 20.
    Pujana, M.A., Han, J.D., Starita, L.M., Stevens, K.N., Tewari, M., Ahn, J.S., Rennert, G., Moreno, V., Kirchhoff, T., Gold, B., Assmann, V., Elshamy, W.M., Rual, J.F., Levine, D., Rozek, L.S., Gelman, R.S., Gunsalus, K.C., Greenberg, R.A., Sobhian, B., Bertin, N., Venkatesan, K., Ayivi-Guedehoussou, N., Solé, X., Hernández, P., Lázaro, C., Nathanson, K.L., Weber, B.L., Cusick, M.E., Hill, D.E., Offit, K., Livingston, D.M., Gruber, S.B., Parvin, J.D., and Vidal, M. (2007) Network modeling links breast cancer susceptibility and centrosome dysfunction Nat Genet 39, 1338–49.PubMedCrossRefGoogle Scholar
  21. 21.
    Xia, K., Xue, H., Dong, D., Zhu, S., Wang, J., Zhang, Q., Hou, L., Chen, H., Tao, R., Huang, Z., Fu, Z., Chen, Y.G., and Han, J.D. (2006) Identification of the proliferation/differentiation switch in the cellular network of multicellular organisms PLoS Comput Biol 2, e145.PubMedCrossRefGoogle Scholar
  22. 22.
    Bertagnolli, M.M. (2009) The forest and the trees: pathways and proteins as colorectal ­cancer biomarkers J Clin Oncol 27(35), 5866–7.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhang, D.Y., Ye, F., Gao, L., Liu, X., Zhao, X., Che, Y., Wang, H., Wang, L., Wu, J., Song, D., Liu, W., Xu, H., Jiang, B., Zhang, W., Wang, J., and Lee, P. (2009) Proteomics, pathway array and signaling network-based medicine in cancer Cell Div 4, 20.PubMedCrossRefGoogle Scholar
  24. 24.
    Ptitsyn, A.A., Weil, M.M., and Thamm, D.H. (2008) Systems biology approach to identification of biomarkers for metastatic progression in cancer BMC Bioinformatics 9 Suppl 9, S8.PubMedCrossRefGoogle Scholar
  25. 25.
    Ideker, T., and Sharan, R. (2008) Protein networks in disease Genome Res 18, 644–52.PubMedCrossRefGoogle Scholar
  26. 26.
    Loscalzo, J., Kohane, I., and Barabasi, A.L. (2007) Human disease classification in the postgenomic era: a complex systems approach to human pathobiology Mol Syst Biol 3, 124.PubMedCrossRefGoogle Scholar
  27. 27.
    Auffray, C. (2007) Protein subnetwork markers improve prediction of cancer outcome Mol Syst Biol 3, 141PubMedCrossRefGoogle Scholar
  28. 28.
    Chuang, H.Y., Lee, E., Liu, Y.T., Lee, D., and Ideker, T. (2007) Network-based classification of breast cancer metastasis Mol Syst Biol 3, 140.PubMedCrossRefGoogle Scholar
  29. 29.
    Wang, E., Lenferink, A., and O’Connor-McCourt, M. (2007) Cancer systems biology: exploring cancer-associated genes on cellular networks Cell Mol Life Sci 64, 1752–62.PubMedCrossRefGoogle Scholar
  30. 30.
    Do, J.H., and Choi, D.K. (2008) Clustering approaches to identifying gene expression patterns from DNA microarray data Mol Cells 25, 279–88.PubMedGoogle Scholar
  31. 31.
    Kerr, G., Ruskin, H.J., Crane, M., and Doolan, P. (2008) Techniques for clustering gene expression data Comput Biol Med 38, 283–93.PubMedCrossRefGoogle Scholar
  32. 32.
    Weeraratna, A.T., and Taub, D.D. (2007) Microarray data analysis: an overview of design, methodology, and analysis Methods Mol Biol 377, 1–16.PubMedCrossRefGoogle Scholar
  33. 33.
    Handl, J., Knowles, J., and Kell, D.B. (2005) Computational cluster validation in post-genomic data analysis Bioinformatics 21, 3201–12.PubMedCrossRefGoogle Scholar
  34. 34.
    Huang, H., Hu, Z.Z., Arighi, C.N., and Wu, C.H. (2007) Integration of bioinformatics resources for functional analysis of gene expression and proteomic data Front Biosci 12, 5071–88.PubMedCrossRefGoogle Scholar
  35. 35.
    Galperin, M.Y., and Cochrane, G.R. (2009) Nucleic Acids Research annual Database Issue and the NAR online Molecular Biology Database Collection in 2009 Nucleic Acids Res 37(Database issue), D1–4.PubMedCrossRefGoogle Scholar
  36. 36.
    UniProt Consortium. (2009) The Universal Protein Resource (UniProt) 2009 Nucleic Acids Res 37(Database issue), D169–74.CrossRefGoogle Scholar
  37. 37.
    Maglott, D., Ostell, J., Pruitt, K.D., and Tatusova, T. (2005) Entrez Gene: gene-centered information at NCBI Nucleic Acids Res 33(Database issue), D54–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Bult, C.J., Kadin, J.A., Richardson, J.E., Blake, J.A., and Eppig, J.T. The Mouse Genome Database Group. (2010) The Mouse Genome Database: enhancements and updates Nucleic Acids Res 38(Database issue), D586–92.PubMedCrossRefGoogle Scholar
  39. 39.
    Barrell, D., Dimmer, E., Huntley, R.P., Binns, D., O’Donovan, C., and Apweiler, R. (2009) The GOA database in 2009 – an integrated Gene Ontology Annotation resource Nucleic Acids Res 37(Database issue), D396–403.PubMedCrossRefGoogle Scholar
  40. 40.
    Kanehisa, M., Araki, M., Goto, S., Hattori, M., Hirakawa, M., Itoh, M., Katayama, T., Kawashima, S., Okuda, S., Tokimatsu, T., and Yamanishi, Y. (2008) KEGG for linking genomes to life and the environment Nucleic Acids Res. 36(Database issue), D480–4.PubMedGoogle Scholar
  41. 41.
    Schaefer, C.F., Anthony, K., Krupa, S., Buchoff, J., Day, M., Hannay, T., and Buetow, K.H. (2009) PID: the Pathway Interaction Database Nucleic Acids Res 37(Database issue), D674–9.PubMedCrossRefGoogle Scholar
  42. 42.
    Aranda, B., Achuthan, P., Alam-Faruque, Y., Armean, I., Bridge, A., Derow, C., Feuermann, M., Ghanbarian, A.T., Kerrien, S., Khadake, J., Kerssemakers, J., Leroy, C., Menden, M., Michaut, M., Montecchi-Palazzi, L., Neuhauser, S.N., Orchard, S., Perreau, V., Roechert, B., van Eijk, K., and Hermjakob, H. (2010) The IntAct molecular interaction database in 2010 Nucleic Acids Res 38(Database issue), D525–31.PubMedCrossRefGoogle Scholar
  43. 43.
    Ceol, A., Chatr Aryamontri, A., Licata, L., Peluso, D., Briganti, L., Perfetto, L., Castagnoli, L., and Cesareni, G. (2010) MINT, the molecular interaction database: 2009 update Nucleic Acids Res 38(Database issue), D532–9.PubMedCrossRefGoogle Scholar
  44. 44.
    Apweiler, R., Bairoch, A., Wu, C.H., Barker, W.C., Boeckmann, B., Ferro, S., Gasteiger, E., Huang, H., Lopez, R., Magrane, M., Martin, M.J., Natale, D.A., O’Donovan, C., Redaschi, N., and Yeh, L.S. (2004) UniProt: the Universal Protein knowledgebase Nucleic Acids Res 32, D115–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Wu, C.H., Huang, H., Nikolskaya, A., Hu, Z., and Barker, W.C. (2004) The iProClass integrated database for protein functional analysis Comput Biol Chem 28, 87–96.PubMedCrossRefGoogle Scholar
  46. 46.
    Huang, da W., Sherman, B.T., Stephens, R., Baseler, M.W., Lane, H.C., and Lempicki, R.A. (2008) DAVID gene ID conversion tool Bioinformation 2, 428–30.Google Scholar
  47. 47.
    Côté, R.G., Jones, P., Martens, L., Kerrien, S., Reisinger, F., Lin, Q., Leinonen, R., Apweiler, R., and Hermjakob, H. (2007) The Protein Identifier Cross-Referencing (PICR) service: reconciling protein identifiers across multiple source databases BMC Bioinformatics 8, 401.PubMedCrossRefGoogle Scholar
  48. 48.
    Sherman, B.T., Huang, da W., Tan, Q., Guo, Y., Bour, S., Liu, D., Stephens, R., Baseler, M.W., Lane, H.C., and Lempicki, R.A. (2007) DAVID Knowledgebase: a gene-centered database integrating heterogeneous gene annotation resources to facilitate high-throughput gene functional analysis BMC Bioinformatics 8, 426.PubMedCrossRefGoogle Scholar
  49. 49.
    Al-Shahrour, F., Carbonell, J., Minguez, P., Goetz, S., Conesa, A., Tárraga, J., Medina, I., Alloza, E., Montaner, D., and Dopazo, J. (2008) Babelomics: advanced functional profiling of transcriptomics, proteomics and genomics experiments Nucleic Acids Res 36(Web Server issue), W341–6.PubMedCrossRefGoogle Scholar
  50. 50.
    Li, Y., and Agarwal, P. (2009) A pathway-based view of human diseases and disease relationships PLoS One 4, e4346.PubMedCrossRefGoogle Scholar
  51. 51.
    Ozgür, A., Vu, T., Erkan, G., and Radev, D.R. (2008) Identifying gene-disease associations using centrality on a literature mined gene-interaction network Bioinformatics 24, i277–85.PubMedCrossRefGoogle Scholar
  52. 52.
    Li, S., Wu, L., and Zhang, Z. (2006) Constructing biological networks through combined literature mining and microarray analysis: a LMMA approach Bioinformatics 22, 2143–50.PubMedCrossRefGoogle Scholar
  53. 53.
    Nikitin, A., Egorov, S., Daraselia, N., and Mazo, I. (2003) Pathway studio – the analysis and navigation of molecular networks Bioinformatics 19, 2155–7.PubMedCrossRefGoogle Scholar
  54. 54.
    Hu, Z.Z., Huang, H., Cheema, A., Jung, M., Dritschilo, A., and Wu, C.H. (2008) Integrated bioinformatics for radiation-induced pathway analysis from proteomics and microarray data J Proteomics Bioinform 1, 47–60.PubMedCrossRefGoogle Scholar
  55. 55.
    Nordlund, P., and Reichard, P. (2006) Ribonucleotide reductases Annu Rev Biochem 75, 681–706.PubMedCrossRefGoogle Scholar
  56. 56.
    Hu, Z.Z., Valencia, J.C., Huang, H., Chi, A., Shabanowitz, J., Hearing, V.J., Appella, E., and Wu, C.H. (2007) Comparative bioinformatics analyses and profiling of lysosome-related organelle proteomes Int J Mass Spectrom 259, 147–60.PubMedCrossRefGoogle Scholar
  57. 57.
    Wheelock, C.E., Wheelock, A.M., Kawashima, S., Diez, D., Kanehisa, M., van Erk, M., Kleemann, R., Haeggström, J.Z., and Goto, S. (2009 ) Systems biology approaches and pathway tools for investigating cardiovascular disease Mol Biosyst 5, 588–602.PubMedCrossRefGoogle Scholar
  58. 58.
    Chi, A., Valencia, J.C., Hu, Z.Z., Watabe, H., Yamaguchi, H., Mangini, N.J., Huang, H., Canfield, V.A., Cheng, K.C., Yang, F., Abe, R., Yamagishi, S., Shabanowitz, J., Hearing, V.J., Wu, C., Appella, E., and Hunt, D.F. (2006) Proteomic and bioinformatic characterization of the biogenesis and ­function of melanosomes J Proteome Res 5, 3135–44.PubMedCrossRefGoogle Scholar
  59. 59.
    Hu, Z.Z., Kagan, B., Huang, H., Liu, H., Jordan, V.C., Riegel, A., Wellstein, A., and Wu, C. (2009) Pathway and Network Analysis of E2-Induced Apoptosis in Breast Cancer Cells 100th AACR Conference, Denver, CO, April 18–22, Abstract #3285.Google Scholar
  60. 60.
    Zhang, Y.W., Jones, T.L., Martin, S.E., Caplen, N.J., and Pommier, Y. (2009) Implication of checkpoint kinase-dependent up-regulation of ribonucleotide reductase R2 in DNA damage response J Biol Chem 284, 18085–95.PubMedCrossRefGoogle Scholar
  61. 61.
    Zhou, B., and Yen, Y. (2001) Characterization of the human ribonucleotide reductase M2 subunit gene; genomic structure and promoter analyses Cytogenet Cell Genet 95, 52–59.PubMedCrossRefGoogle Scholar
  62. 62.
    Zhou, B., Tsai, P., Ker, R., Tsai, J., Ho, R., Yu, J., Shih, J., and Yen, Y. (1998) Overexpression of transfected human ribonucleotide reductase M2 subunit in human cancer cells enhances their invasive potential Clin Exp Metastasis 16, 43–9.PubMedCrossRefGoogle Scholar
  63. 63.
    Ransohoff, D.F. (2009). Promises and limitations of biomarkers Recent Results Cancer Res 181, 55–9.PubMedCrossRefGoogle Scholar
  64. 64.
    Waters, K.M., Pounds, J.G., and Thrall, B.D. (2006) Data merging for integrated microarray and proteomic analysis Brief Funct Genomic Proteomic 5, 261–72.PubMedCrossRefGoogle Scholar
  65. 65.
    Wu, C.H., Apweiler, R., Bairoch, A., Natale, D.A., Barker, W.C., Boeckmann, B., Ferro, S., Gasteiger, E., Huang, H., Lopez, R., Magrane, M., Martin, M.J., Mazumder, R., O’Donovan, C., Redaschi, N., Suzek, B. (2006) The Universal Protein Resource (UniProt): an expanding universe of protein information Nucleic Acids Res 34(Database issue), D187–91.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Zhang-Zhi Hu
    • 1
    Email author
  • Hongzhan Huang
    • 2
  • Cathy H. Wu
    • 2
  • Mira Jung
    • 1
  • Anatoly Dritschilo
    • 1
  • Anna T. Riegel
    • 1
  • Anton Wellstein
    • 1
  1. 1.Lombardi Cancer CenterGeorgetown UniversityWashingtonUSA
  2. 2.Center for Bioinformatics & Computational BiologyUniversity of DelawareNewarkUSA

Personalised recommendations