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Spotlight on Molecular Targeted Therapy

Large-scale gene expression analysis in molecular target discovery

Leukemia volume 16, pages 473–477 (2002)Cite this article

Abstract

The evolution of simple arrays consisting of a few genes to ones composed of thousands of genes and/or ESTs has allowed investigators unprecedented views of the molecular mechanisms within cells. Due to the enormous quantities of information derived from microarray analysis, new types of problems have surfaced, such as where to store all of the data. The ability to solve database or statistical problems has required the bench biologist to collaborate with database developers, software designers and statisticians to determine solutions for storage, analysis and interpretation of microarray data. The collaborative effort between these extremely diverse disciplines has led to the development of creative database query and gene expression analysis tools, producing significant reductions in the time required by researchers to filter through the datasets and discover the key processes perturbed by the diseases of interest. Both unsupervised and supervised analysis methods have been applied to gene expression data leading to the discovery of novel therapeutic targets and diagnostic markers. Furthermore, tumor classification based on their respective molecular fingerprints has led to the classification of cancer subtypes and the discovery of novel molecular taxonomies that may eventually lead to improved patient stratification and superior therapeutic strategies.

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References

  1. Velculescu VE, Zhang L, Vogelstein B, Kinzler KW . Serial analysis of gene expression Science 1995 270: 484–487

    Article  CAS  PubMed  Google Scholar 

  2. Prashar Y, Weissman SM . Analysis of differential gene expression by display of 3’ end restriction fragments of cDNAs Proc Natl Acad Sci USA 1996 93: 659–663

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Schena M, Shalon D, Davis RW, Brown PO . Quantitative monitoring of gene expression patterns with a complementary DNA microarray Science 1995 270: 467–470

    Article  CAS  PubMed  Google Scholar 

  4. Fodor SP, Read JL, Pirrung MC, Stryer L, Lu AT, Solas D . Light-directed, spatially addressable parallel chemical synthesis Science 1991 251: 767–773

    Article  CAS  PubMed  Google Scholar 

  5. Gerhold D, Lu M, Xu J, Austin C, Caskey CT, Rushmore T . Monitoring expression of genes involved in drug metabolism and toxicology using DNA microarrays Physiol Genomics 2001 5: 161–170

    Article  CAS  PubMed  Google Scholar 

  6. Guo Z, Guilfoyle RA, Thiel AJ, Wang R, Smith LM . Direct fluorescence analysis of genetic polymorphisms by hybridization with oligonucleotide arrays on glass supports Nucleic Acids Res 1994 22: 5456–5465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hughes TR, Mao M, Jones AR, Burchard J, Marton MJ, Shannon KW, Lefkowitz SM, Ziman M, Schelter JM, Meyer MR, Kobayashi S, Davis C, Dai H, He YD, Stephaniants SB, Cavet G, Walker WL, West A, Coffey E, Shoemaker DD, Stoughton R, Blanchard AP, Friend SH, Linsley PS . Expression profiling using microarrays fabricated by an ink-jet oligonucleotide synthesizer Nat Biotechnol 2001 19: 342–347

    Article  CAS  PubMed  Google Scholar 

  8. Spellman PT, Sherlock G, Zhang MQ, Iyer VR, Anders K, Eisen MB, Brown PO, Botstein D, Futcher B . Comprehensive identification of cell cycle-regulated genes of the yeast Saccharomyces cerevisiae by microarray hybridization Mol Biol Cell 1998 9: 3273–3297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Eisen MB, Spellman PT, Brown PO, Botstein D . Cluster analysis and display of genome-wide expression patterns Proc Natl Acad Sci USA 1998 95: 14863–14868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Eisen MB, Spellman PT, Brown PO, Botstein D . Cluster analysis and display of genome-wide expression patterns Proc Natl Acad Sci USA 1999 96: 10943c

    Google Scholar 

  11. Weinstein JN, Myers TG, O'Connor PM, Friend SH, Fornace AJ, Kohn KW, Fojo T, Bates SE, Rubinstein LV, Anderson NL, Buolamwini JK, van Osdol WW, Monks AP, Scudiero DA, Sausville EA, Zaharevitz DW, Bunow B, Viswanadhan VN, Johnson GS, Wittes RE, Paull KD . An information-intensive approach to the molecular pharmacology of cancer Science 1997 275: 343–349

    Article  CAS  PubMed  Google Scholar 

  12. Wen X, Fuhrman S, Michaels GS, Carr DB, Smith S, Barker JL, Somogyi R . Large-scale temporal gene expression mapping of central nervous system development Proc Natl Acad Sci USA 1998 95: 334–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Cho RJ, Campbell MJ, Winzeler EA, Steinmetz L, Conway A, Wodicka L, Wolfsberg TG, Gabrielian AE, Landsman D, Lockhart DJ, Davis RW . A genome-wide transcriptional analysis of the mitotic cell cycle Mol Cell 1998 2: 65–73

    Article  CAS  PubMed  Google Scholar 

  14. Iyer VR, Eisen MB, Ross DT, Schuler G, Moore T, Lee JCF, Trent JM, Staudt LM, Hudson J Jr, Boguski MS, Lashkari D, Shalon D, Botstein D, Brown PO . The transcriptional program in the response of human fibroblasts to serum Science 1999 283: 83–87

    Article  CAS  PubMed  Google Scholar 

  15. Alon U, Barkai N, Notterman DA, Gish K, Ybarra S, Mack D, Levine AJ . Broad patterns of gene expression revealed by clustering analysis of tumor and normal colon tissues probed by oligonucleotide arrays Proc Natl Acad Sci USA 1999 96: 6745–6750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM . Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling Nature 2000 403: 503–511

    Article  CAS  PubMed  Google Scholar 

  17. Ross DT, Scherf U, Eisen MB, Perou CM, Rees C, Spellman P, Iyer V, Jeffrey SS, Van de Rijn M, Waltham M, Pergamenschikov A, Lee JC, Lashkari D, Shalon D, Myers TG, Weinstein JN, Botstein D, Brown PO . Systematic variation in gene expression patterns in human cancer cell lines Nat Genet 2000 24: 227–235

    Article  CAS  PubMed  Google Scholar 

  18. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D . Molecular portraits of human breast tumours Nature 2000 406: 747–752

    Article  CAS  PubMed  Google Scholar 

  19. Raychaudhuri S, Stuart JM, Altman RB . Principal components analysis to summarize microarray experiments: application to sporulation time series Pac Symp Biocomput 2000 455–466

  20. Hilsenbeck SG, Friedrichs WE, Schiff R, O'Connell P, Hansen RK, Osborne CK, Fuqua SA . Statistical analysis of array expression data as applied to the problem of tamoxifen resistance J Natl Cancer Inst 1999 91: 453–459

    Article  CAS  PubMed  Google Scholar 

  21. Chu S, DeRisi J, Eisen M, Mulholland J, Botstein D, Brown PO, Herskowitz I . The transcriptional program of sporulation in budding yeast Science 1998 282: 699–705

    Article  CAS  PubMed  Google Scholar 

  22. Xiong M, Jin L, Li W, Boerwinkle E . Computational methods for gene expression-based tumor classification Biotechniques 2000 29: 1264–1270

    Article  CAS  PubMed  Google Scholar 

  23. Khan J, Wei JS, Ringner M, Saal LH, Ladanyi M, Westermann F, Berthold F, Schwab M, Antonescu CR, Peterson C, Meltzer PS . Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks Nat Med 2001 7: 673–679

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Khan J, Simon R, Bittner M, Chen Y, Leighton S, Pohida T, Smith P, Jiang Y, Gooden G, Trent J, Meltzer P . Gene expression profiling of alveolar rhabdomyosarcoma with cDNA microarrays Cancer Res 1998 58: 5009–5013

    CAS  PubMed  Google Scholar 

  25. Bittner M, Meltzer P, Chen Y, Jiang Y, Seftor E, Hendrix M, Radmacher M, Simon R, Yakhini Z, Ben-Dor A, Sampas N, Dougherty E, Wang E, Marincola F, Gooden C, Lueders J, Glatfelter A, Pollock P, Carpten J, Gillanders E, Leja D, Dietrich K, Beaudry C, Berens M, Alberts D, Sondak V . Molecular classification of cutaneous malignant melanoma by gene expression profiling Nature 2000 406: 536–540

    Article  CAS  PubMed  Google Scholar 

  26. Hedenfalk I, Duggan D, Chen Y, Radmacher M, Bittner M, Simon R, Meltzer P, Gusterson B, Esteller M, Kallioniemi OP, Wilfond B, Borg A, Trent J . Gene-expression profiles in hereditary breast cancer N Engl J Med 2001 344: 539–548

    Article  CAS  PubMed  Google Scholar 

  27. Dunn WJ III, Wold S . Structure–activity study of beta-adrenergic agents using the SIMCA method of pattern recognition J Med Chem 1978 21: 922–930

    Article  CAS  PubMed  Google Scholar 

  28. Holmes E, Nicholls AW, Lindon JC, Connor SC, Connelly JC, Haselden JN, Damment SJ, Spraul M, Neidig P, Nicholson JK . Chemometric models for toxicity classification based on NMR spectra of biofluids Chem Res Toxicol 2000 13: 471–478

    Article  CAS  PubMed  Google Scholar 

  29. Unger PD, Watson CW, Liu Z, Gil J . Morphometric analysis of neoplastic renal aspirates and benign renal tissue Anal Quant Cytol Histol 1993 15: 61–66

    CAS  PubMed  Google Scholar 

  30. Yeang CH, Ramaswamy S, Tamayo P, Mukherjee S, Rifkin RM, Angelo M, Reich M, Lander E, Mesirov J, Golub T . Molecular classification of multiple tumor types Bioinformatics 2001 17 (Suppl. 1): S316–S322

    Article  Google Scholar 

  31. Brown MP, Grundy WN, Lin D, Cristianini N, Sugnet CW, Furey TS, Ares M Jr, Haussler D . Knowledge-based analysis of microarray gene expression data by using support vector machines Proc Natl Acad Sci USA 2000 97: 262–267

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Weinstein JN, Kohn KW, Grever MR, Viswanadhan VN, Rubinstein LV, Monks AP, Scudiero DA, Welch L, Koutsoukos AD, Chiausa AJ, Paull KD . Neural computing in cancer drug development: predicting mechanism of action Science 1992 258: 447–451

    Article  CAS  PubMed  Google Scholar 

  33. Gruvberger S, Ringner M, Chen Y, Panavally S, Saal LH, Borg A, Ferno M, Peterson C, Meltzer PS . Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns Cancer Res 2001 61: 5979–5984

    CAS  PubMed  Google Scholar 

  34. Hastie T, Tibshirani R, Eisen MB, Alizadeh A, Levy R, Staudt L, Chan WC, Botstein D, Brown P . ‘Gene shaving’ as a method for identifying distinct sets of genes with similar expression patterns Genome Biol 2000 1: 2

    Article  Google Scholar 

  35. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP, Coller H, Loh ML, Downing JR, Caligiuri MA, Bloomfield CD, Lander ES . Molecular classification of cancer: class discovery and class prediction by gene expression monitoring Science 1999 286: 531–537

    Article  CAS  PubMed  Google Scholar 

  36. Scherf U, Ross DT, Waltham M, Smith LH, Lee JK, Tanabe L, Kohn KW, Reinhold WC, Myers TG, Andrews DT, Scudiero DA, Eisen MB, Sausville EA, Pommier Y, Botstein D, Brown PO, Weinstein JN . A gene expression database for the molecular pharmacology of cancer Nat Genet 2000 24: 236–244

    Article  CAS  PubMed  Google Scholar 

  37. Fischel JL, Etienne MC, Spector T, Formento P, Renee N, Milano G . Dihydropyrimidine dehydrogenase: a tumoral target for fluorouracil modulation Clin Cancer Res 1995 1: 991–996

    CAS  PubMed  Google Scholar 

  38. McLeod HL, Sludden J, Murray GI, Keenan RA, Davidson AI, Park K, Koruth M, Cassidy J . Characterization of dihydropyrimidine dehydrogenase in human colorectal tumours Br J Cancer 1998 77: 461–465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Cooney DA, Handschumacher RE . L-asparaginase and L-asparagine metabolism Annu Rev Pharmacol 1970 10: 421–440

    Article  CAS  PubMed  Google Scholar 

  40. Capizzi RL, Bertino JR, Handschumacher RE . L-asparaginase Annual Rev Med 1970 21: 433–444

    Article  CAS  Google Scholar 

  41. Wada H, Imamura I, Sako M, Katagiri S, Tarui S, Nishimura H, Inada Y . Antitumor enzyme: polyethylene glycol-modified asparaginase Ann NY Acad Sci 1990 613: 95–108

    Article  CAS  PubMed  Google Scholar 

  42. Maltzman W, Czyzyk L . UV irradiation stimulates levels of p53 cellular tumor antigen in nontransformed mouse cells Mol Cell Biol 1984 4: 1689–1694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW . Participation of p53 protein in the cellular response to DNA damage Cancer Res 1991 51: 6304–6311

    CAS  PubMed  Google Scholar 

  44. Sakaguchi K, Herrera JE, Saito S, Miki T, Bustin M, Vassilev A, Anderson CW, Appella E . DNA damage activates p53 through a phosphorylation-acetylation cascade Genes Dev 1998 12: 2831–2841

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. O'Connor PM, Jackman J, Jondle D, Bhatia K, Magrath I, Kohn KW . Role of the p53 tumor suppressor gene in cell cycle arrest and radiosensitivity of Burkitt's lymphoma cell lines Cancer Res 1993 53: 4776–4780

    CAS  PubMed  Google Scholar 

  46. Siliciano JD, Canman CE, Taya Y, Sakaguchi K, Appella E, Kastan MB . DNA damage induces phosphorylation of the amino terminus of p53 Genes Dev 1997 11: 3471–3481

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S, Torhorst J, Mihatsch MJ, Sauter G, Kallioniemi OP . Tissue microarrays for high-throughput molecular profiling of tumor specimens Nat Med 1998 4: 844–847

    Article  CAS  PubMed  Google Scholar 

  48. Kallioniemi OP, Wagner U, Kononen J, Sauter G . Tissue microarray technology for high-throughput molecular profiling of cancer Hum Mol Genet 2001 10: 657–662

    Article  CAS  PubMed  Google Scholar 

  49. Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, Kurachi K, Pienta KJ, Rubin MA, Chinnaiyan AM . Delineation of prognostic biomarkers in prostate cancer Nature 2001 412: 822–826

    Article  CAS  PubMed  Google Scholar 

  50. Horvath L, Henshall S . The application of tissue microarrays to cancer research Pathology 2001 33: 125–129

    Article  CAS  PubMed  Google Scholar 

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    MS Orr & U Scherf

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Orr, M., Scherf, U. Large-scale gene expression analysis in molecular target discovery. Leukemia 16, 473–477 (2002). https://doi.org/10.1038/sj.leu.2402413

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