Skip to main content

Bioinformatics Approaches to Cancer Gene Discovery

  • Protocol
Target Discovery and Validation Reviews and Protocols

Part of the book series: Methods in Molecular Biology™ ((MIMB,volume 360))

  • 2164 Accesses

Summary

The Cancer Gene Anatomy Project (CGAP) database of the National Cancer Institute has thousands of known and novel expressed sequence tags (ESTs). These ESTs, derived from diverse normal and tumor cDNA libraries, offer an attractive starting point for cancer gene discovery. Data-mining the CGAP database led to the identification of ESTs that were predicted to be specific to select solid tumors. Two genes from these efforts were taken to proof of concept for diagnostic and therapeutics indications of cancer. Microarray technology was used in conjunction with bioinformatics to understand the mechanism of one of the targets discovered. These efforts provide an example of gene discovery by using bioinformatics approaches. The strengths and weaknesses of this approach are discussed in this review.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Andrade, M. A. and Sander, C. (1997) Bioinformatics: from genome data to biological knowledge. Curr. Opin. Biotechnol. 8, 675–683.

    Article  CAS  PubMed  Google Scholar 

  2. Cavalli-Sforza, L. L. (2005) The Human Genome Diversity Project: past, present and future. Nat. Rev. Genet. 6, 333–340.

    CAS  PubMed  Google Scholar 

  3. Collins, F. S., Patrinos, A., Jordan, E., Chakravarti, A., Gesteland, R., and Walters, L. (1998) New goals for the U.S. Human Genome Project: 1998–2003. Science 282, 682–689.

    Article  CAS  PubMed  Google Scholar 

  4. Robbins, R. J. (1996) Bioinformatics: essential infrastructure for global biology. J. Comput. Biol. 3, 465–478.

    Article  CAS  PubMed  Google Scholar 

  5. Fannon, M. R. (1996) Gene expression in normal and disease states—identification of therapeutic targets. Trends Biotechnol. 14, 294–298.

    Article  CAS  PubMed  Google Scholar 

  6. Elek, J., Park, K. H., and Narayanan, R. (2000) Microarray-based expression profiling in prostate tumors. In Vivo 14, 173–182.

    CAS  PubMed  Google Scholar 

  7. Heller, R. A., Schena, M., Chai, A., et al. (1997) Discovery and analysis of inflammatory disease-related genes using cDNA microarrays. Proc. Natl. Acad. Sci. USA 94, 2150–2155.

    Article  CAS  PubMed  Google Scholar 

  8. Khan, J., Bittner, M. L., Saal, L. H., et al. (1999) cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene. Proc. Natl. Acad. Sci. USA 96, 13,264–13,269.

    Article  CAS  PubMed  Google Scholar 

  9. Lockhart, D. J., Dong, H., Byrne, M. C., et al. (1996) Expression monitoring by hybridization to high-density oligonucleotide arrays. Nat. Biotechnol. 14, 1675–1680.

    Article  CAS  PubMed  Google Scholar 

  10. Lal, A., Lash, A. E., Altschul, S. F., et al. (1999) A public database for gene expression in human cancers. Cancer Res. 59, 5403–5407.

    CAS  PubMed  Google Scholar 

  11. Nacht, M., Ferguson, A. T., Zhang, W., et al. (1999) Combining serial analysis of gene expression and array technologies to identify genes differentially expressed in breast cancer. Cancer Res. 59, 5464–5470.

    CAS  PubMed  Google Scholar 

  12. Strausberg, R. L., Dahl, C. A., and Klausner, R. D. (1997) New opportunities for uncovering the molecular basis of cancer. Nat. Genet. 15, 415–416.

    Article  CAS  PubMed  Google Scholar 

  13. Wheeler, D. L., Chappey, C., Lash, A. E., et al. (2000) Database resources of the National Center for Biotechnology Information. Nucleic Acids Res. 28, 10–14.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang, L., Zhou, W., Velculescu, V. E., et al. (1997) Gene expression profiles in normal and cancer cells. Science 276, 1268–1272.

    Article  CAS  PubMed  Google Scholar 

  15. Schmitt, A. O., Specht, T., Beckmann, G., et al. (1999) Exhaustive mining of EST libraries for genes differentially expressed in normal and tumour tissues. Nucleic Acids Res. 27, 4251–4260.

    Article  CAS  PubMed  Google Scholar 

  16. Scheurle, D., DeYoung, M. P., Binninger, D. M., Page, H., Jahanzeb, M., and Narayanan, R. (2000) Cancer gene discovery using digital differential display. Cancer Res. 60, 4037–4043.

    CAS  PubMed  Google Scholar 

  17. DeYoung, M. P., Damania, H., Scheurle, D., Zylberberg, C., and Narayanan, R. (2002) Bioinformatics-based discovery of a novel factor with apparent specificity to colon cancer. In Vivo 16, 239–248.

    CAS  Google Scholar 

  18. Holcomb, I. N., Kabakoff, R. C., Chan, B., et al. (2000) FIZZ1, a novel cysteine-rich secreted protein associated with pulmonary inflammation, defines a new gene family. EMBO J. 19, 4046–4055.

    Article  CAS  PubMed  Google Scholar 

  19. Steppan, C. M., Bailey, S. T., Bhat, S., et al. (2001) The hormone resistin links obesity to diabetes. Nature 409, 307–312.

    Article  CAS  PubMed  Google Scholar 

  20. Steppan, C. M., Brown, E. J., Wright, C. M., et al. (2001) A family of tissue-specific resistin-like molecules. Proc. Natl. Acad. Sci. USA 98, 502–506.

    Article  CAS  PubMed  Google Scholar 

  21. Su, A. I., Cooke, M. P., Ching, K. A., et al. (2002) Large-scale analysis of the human and mouse transcriptomes. Proc. Natl. Acad. Sci. USA 99, 4465–4470.

    Article  CAS  PubMed  Google Scholar 

  22. He, W., Wang, M. L., Jiang, H. Q., et al. (2003) Bacterial colonization leads to the colonic secretion of RELMbeta/FIZZ2, a novel goblet cell-specific protein. Gastroenterology 125, 1388–1397.

    Article  CAS  PubMed  Google Scholar 

  23. Kubota, T., Kawano, S., Chih, D. Y., et al. (2000) Representational difference analysis using myeloid cells from C/EBP epsilon deletional mice. Blood 96, 3953–3957.

    CAS  PubMed  Google Scholar 

  24. Blagoev, B., Kratchmarova, I., Nielsen, M. M., et al. (2002) Inhibition of adipocyte differentiation by resistin-like molecule alpha. Biochemical characterization of its oligomeric nature. J Biol Chem. 277, 42,011–42,016.

    Article  CAS  PubMed  Google Scholar 

  25. Teng, X., Li, D., Champion, H. C., and Johns, R. A. (2003) FIZZ1/RELMalpha, a novel hypoxia-induced mitogenic factor in lung with vasoconstrictive and angiogenic properties. Circ. Res. 92, 1065–1067.

    Article  CAS  PubMed  Google Scholar 

  26. Chrast, R., Scott, H. S., Chen, H., et al. (1997) Cloning of two human homologs of the Drosophila single-minded gene SIM1 on chromosome 6q and SIM2 on 21q within the Down syndrome chromosomal region. Genome Res. 7, 615–624.

    CAS  PubMed  Google Scholar 

  27. Dahmane, N., Charron, G., Lopes, C., et al. (1995) Down syndrome-critical region contains a gene homologous to Drosophila sim expressed during rat and human central nervous system development. Proc. Natl. Acad. Sci. USA 92, 9191–9195.

    Article  CAS  PubMed  Google Scholar 

  28. Frazer, K. A., Tao, H., Osoegawa, K., et al. (2004) Noncoding sequences conserved in a limited number of mammals in the SIM2 interval are frequently functional. Genome Res. 14, 367–372.

    Article  CAS  PubMed  Google Scholar 

  29. Crews, S. T. and Fan, C. M. (1999) Remembrance of things PAS: regulation of development by bHLH-PAS proteins. Curr. Opin. Genet. Dev. 9, 580–587.

    Article  CAS  PubMed  Google Scholar 

  30. Taylor, B. L. and Zhulin, I. B. (1999) PAS domains: internal sensors of oxygen, redox potential, and light. Microbiol. Mol. Biol. Rev. 63, 479–506.

    CAS  PubMed  Google Scholar 

  31. Ema, M., Morita, M., Ikawa, S., et al. (1996) Two new members of the murine Sim gene family are transcriptional repressors and show different expression patterns during mouse embryogenesis. Mol. Cell Biol. 16, 5865–5875.

    CAS  PubMed  Google Scholar 

  32. Michaud, J. L., DeRossi, C., May, N. R., Holdener, B. C., and Fan, C. M. (2000) ARNT2 acts as the dimerization partner of SIM1 for the development of the hypothalamus. Mech. Dev. 90, 253–261.

    Article  CAS  PubMed  Google Scholar 

  33. Pongratz, I., Antonsson, C., Whitelaw, M. L., and Poellinger, L. (1998) Role of the PAS domain in regulation of dimerization and DNA binding specificity of the dioxin receptor. Mol. Cell. Biol 18, 4079–4088.

    CAS  PubMed  Google Scholar 

  34. Moffett, P. and Pelletier, J. (2000) Different transcriptional properties of mSim-1 and mSim-2. FEBS Lett. 466, 80–86.

    Article  CAS  PubMed  Google Scholar 

  35. Probst, M. R., Fan, C. M., Tessier-Lavigne, M., and Hankinson, O. (1997) Two murine homologs of the Drosophila single-minded protein that interact with the mouse aryl hydrocarbon receptor nuclear translocator protein. J. Biol. Chem. 272, 4451–4457.

    Article  CAS  PubMed  Google Scholar 

  36. Swanson, H. I., Chan,W. K., and Bradfield, C. A. (1995) DNA binding specificities and pairing rules of the Ah receptor, ARNT, and SIM proteins. J. Biol. Chem. 270, 26,292–26,302.

    Article  CAS  PubMed  Google Scholar 

  37. Ooe, N., Saito, K., Mikami, N., Nakatuka, I., and Kaneko, H. (2004) Identification of a novel basic helix-loop-helix-PAS factor, NXF, reveals a Sim2 competitive, positive regulatory role in dendritic-cytoskeleton modulator drebrin gene expression. Mol. Cell. Biol. 24, 608–616.

    Article  CAS  PubMed  Google Scholar 

  38. Yamaki, A., Kudoh, J., Shimizu, N., and Shimizu, Y. (2004) A novel nuclear localization signal in the human single-minded proteins SIM1 and SIM2. Biochem. Biophys. Res. Commun. 313, 482–488.

    Article  CAS  PubMed  Google Scholar 

  39. Madden, S. L., Cook, D. M., Morris, J. F., Gashler, A., Sukhatme, V. P., and Rauscher, F. J., III (1991) Transcriptional repression mediated by the WT1 Wilms tumor gene product. Science 253, 1550–1553.

    Article  CAS  PubMed  Google Scholar 

  40. Franks, R. G. and Crews, S. T. (1994) Transcriptional activation domains of the single-minded bHLH protein are required for CNS midline cell development. Mech. Dev. 45, 269–277.

    Article  CAS  PubMed  Google Scholar 

  41. Mermod, N., O’Neill, E. A., Kelly, T. J., and Tjian, R. (1989) The proline-rich transcriptional activator of CTF/NF-I is distinct from the replication and DNA binding domain. Cell 58, 741–753.

    Article  CAS  PubMed  Google Scholar 

  42. Hanna-Rose, W. and Hansen, U. (1996) Active repression mechanisms of eukaryotic transcription repressors. Trends Genet. 12, 229–234.

    Article  CAS  PubMed  Google Scholar 

  43. DeYoung, M. P., Scheurle, D., Damania, H., Zylberberg, Z., and Narayanan, R. (2002) Down’s syndrome-associated Single Minded gene as a novel tumor marker. Anticancer Res. 22, 3149–3158.

    CAS  PubMed  Google Scholar 

  44. DeYoung, M. P., Tress, M., and Narayanan, R. (2003) Identification of Down’s syndrome critical locus gene SIM2-s as a drug therapy target for solid tumors. Proc. Natl. Acad. Sci. USA 100, 4760–4765.

    Article  CAS  PubMed  Google Scholar 

  45. DeYoung, M. P., Tress, M., and Narayanan, R. (2003) Down’s syndrome-associated Single Minded 2 gene as a pancreatic cancer drug therapy target. Cancer Lett. 200, 25–31.

    Article  CAS  PubMed  Google Scholar 

  46. Goolsby, M. J. (2001) Use of PSA measurement in practice. J. Am. Acad. Nurse Pract. 13, 246–248.

    Article  CAS  PubMed  Google Scholar 

  47. Aleman, M. J., DeYoung, M. P., Tress, M., Keating, P., Perry, G. W., and Narayanan, R. (2005) Inhibition of single minded 2 gene expression mediates tumor-selective apoptosis and differentiation in human colon cancer cells. Proc. Natl. Acad. Sci. USA 102, 12,765–12,770.

    Article  CAS  PubMed  Google Scholar 

  48. Ratan, R. R. (2003) Mining genome databases for therapeutic gold: SIM2 is a novel target for treatment of solid tumors. Trends Pharmacol. Sci. 24, 508–510.

    Article  CAS  PubMed  Google Scholar 

  49. Touchette, N. (2003) Mouse-to-mouse revelation: genome yields cancer drug target. Genome News Network. http://www.genomenewsnetwork.org/articles/04_03.mouse.shtml. April 18, 2003.

  50. Nambu, J. R., Lewis, J. O., Wharton, K. A., Jr., and Crews, S. T. (1991) The Drosophila single-minded gene encodes a helix-loop-helix protein that acts as a master regulator of CNS midline development. Cell 67, 1157–1167.

    Article  CAS  PubMed  Google Scholar 

  51. Benbow, L., Wang, L., Laverty, M., et al. (2002) A reference database for tumor-related genes co-expressed with interleukin-8 using genome-scale in silico analysis. BMC Genomics 3, 29.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

I thank members of my laboratory for valuable contributions and Jeanine Narayanan for editorial assistance.

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Humana Press Inc.

About this protocol

Cite this protocol

Narayanan, R. (2007). Bioinformatics Approaches to Cancer Gene Discovery. In: Sioud, M. (eds) Target Discovery and Validation Reviews and Protocols. Methods in Molecular Biology™, vol 360. Humana Press. https://doi.org/10.1385/1-59745-165-7:13

Download citation

  • DOI: https://doi.org/10.1385/1-59745-165-7:13

  • Publisher Name: Humana Press

  • Print ISBN: 978-1-58829-656-6

  • Online ISBN: 978-1-59745-165-9

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics