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  • Perspective
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Cancer genomics: from discovery science to personalized medicine

Nature Medicine volume 17, pages 297–303 (2011)Cite this article

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Abstract

Recent advances in genome technologies and the ensuing outpouring of genomic information related to cancer have accelerated the convergence of discovery science and clinical medicine. Successful examples of translating cancer genomics into therapeutics and diagnostics reinforce its potential to make possible personalized cancer medicine. However, the bottlenecks along the path of converting a genome discovery into a tangible clinical endpoint are numerous and formidable. In this Perspective, we emphasize the importance of establishing the biological relevance of a cancer genomic discovery in realizing its clinical potential and discuss some of the major obstacles to moving from the bench to the bedside.

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Figure 1: Cancer genetics is accelerating the time from 'driver mutation discovery' to 'clinical proof-of-concept' and the approval of new drugs.
Figure 2: From cancer genomics to personalized medicine.
Figure 3: Trade-off among commonly used experimental systems for functional validation.

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References

  1. Reddy, E.P., Reynold, R.K., Santos, E. & Barbacid, M. A point mutation is responsible for the acquisition of transforming properties of the T24 human bladder carcinoma oncogene. Nature 300, 149–152 (1982).

    Google Scholar 

  2. Tabin, C.J. Mechanism of activation of a human oncogene. Nature 300, 143–149 (1982).

    Google Scholar 

  3. Capon, D.J. et al. Activation of Ki-ras2 gene in human colon and lung carcinomas by two different point mutations. Nature 304, 507–513 (1983).

    Google Scholar 

  4. McGrath, J.P. et al. Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene. Nature 304, 501–506 (1983).

    Google Scholar 

  5. Shimizu, K. et al. Structure of the Ki-ras gene of the human lung carcinoma cell line Calu-1. Nature 304, 497–500 (1983).

    Google Scholar 

  6. Bos, J.L. et al. Amino-acid substitutions at codon 13 of the N-ras oncogene in human acute myeloid leukaemia. Nature 315, 726–730 (1985).

    Google Scholar 

  7. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 3, 11–22 (2003).

    Google Scholar 

  8. Sousa, S.F., Fernandes, P.A. & Ramos, M.J. Farnesyltransferase inhibitors: a detailed chemical view on an elusive biological problem. Curr. Med. Chem. 15, 1478–1492 (2008).

    Google Scholar 

  9. Haura, E.B. et al. A phase II study of PD-0325901, an oral MEK inhibitor, in previously treated patients with advanced non-small cell lung cancer. Clin. Cancer Res. 16, 2450–2457 (2010)

    Google Scholar 

  10. Allegra, C.J. et al. American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J. Clin. Oncol. 27, 2091–2096 (2009).

    Google Scholar 

  11. Lièvre, A. et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J. Clin. Oncol. 26, 374–379 (2008).

    Google Scholar 

  12. Amado, R.G. et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J. Clin. Oncol. 26, 1626–1634 (2008).

    Google Scholar 

  13. Eberhard, D.A. et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J. Clin. Oncol. 23, 5900–5909 (2005).

    Google Scholar 

  14. Futreal, P.A. et al. A census of human cancer genes. Nat. Rev. Cancer 4, 177–183 (2004).

    Google Scholar 

  15. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).

    Google Scholar 

  16. Flaherty, K.T. et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 363, 809–819 (2010).

    Google Scholar 

  17. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 504–508, (2004).

    Google Scholar 

  18. Bachman, K.E. A.P., Samuels, Y., Silliman, N., Ptak, J., Szabo, S., Konishi, H., Karakas, B., Blair, B.G., Lin, C., Peters, A.B., Velculescu, V.E. & Park, B.H. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther. 3, 772–775 (2004).

    Google Scholar 

  19. Campbell, I.G. et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 64, 7678–7681 (2004).

    Google Scholar 

  20. Brachmann, S., Fritsch, C., Maira, S.-M. & García-Echeverría, C. PI3K and mTOR inhibitors—a new generation of targeted anticancer agents. Curr. Opin. Cell Biol. 21, 194–198 (2009).

    Google Scholar 

  21. The Cancer Genome Atlas Research Network. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455, 1061–1068 (2008).

  22. Jaiswal, B.S. et al. Somatic mutations in p85α promote tumorigenesis through class IA PI3K activation. Cancer Cell 16, 463–474 (2009).

    Google Scholar 

  23. Zhao, L. & Vogt, P.K. Helical domain and kinase domain mutations in p110α of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc. Natl. Acad. Sci. USA 105, 2652–2657 (2008).

    Google Scholar 

  24. Turke, A.B. & Engelman, J.A. PIKing the right patient. Clin. Cancer Res. 16, 3523–3525 (2010).

    Google Scholar 

  25. Courtney, K.D., Corcoran, R.B. & Engelman, J.A. The PI3K pathway as drug target in human cancer. J. Clin. Oncol. 28, 1075–1083 (2010).

    Google Scholar 

  26. Kralovics, R. et al. A gain-of-function mutation of JAK2 in myeloproliferative disorders. N. Engl. J. Med. 352, 1779–1790 (2005).

    Google Scholar 

  27. Levine, R.L. et al. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7, 387–397 (2005).

    Google Scholar 

  28. Verstovsek, S. et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N. Engl. J. Med. 363, 1117–1127 (2010).

    Google Scholar 

  29. Curtin, J.A., Busam, K., Pinkel, D. & Bastian, B.C. Somatic activation of KIT in distinct subtypes of melanoma. J. Clin. Oncol. 24, 4340–4346 (2006).

    Google Scholar 

  30. Dutt, A. et al. Drug-sensitive FGFR2 mutations in endometrial carcinoma. Proc. Natl. Acad. Sci. USA 105, 8713–8717 (2008).

    Google Scholar 

  31. Pollock, P.M. et al. Frequent activating FGFR2 mutations in endometrial carcinomas parallel germline mutations associated with craniosynostosis and skeletal dysplasia syndromes. Oncogene 26, 7158–7162 (2007).

    Google Scholar 

  32. Handolias, D. et al. Clinical responses observed with imatinib or sorafenib in melanoma patients expressing mutations in KIT. Br. J. Cancer 102, 1219–1223 (2010).

    Google Scholar 

  33. Van Raamsdonk, C.D. et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457, 599–602 (2009).

    Google Scholar 

  34. Stephens, P. et al. Lung cancer: intragenic ERBB2 kinase mutations in tumours. Nature 431, 525–526 (2004).

    Google Scholar 

  35. Slamon, D.J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).

    Google Scholar 

  36. Lynch, T.J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).

    Google Scholar 

  37. Parsons, D.W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    Google Scholar 

  38. Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    Google Scholar 

  39. Reitman, Z.J. & Yan, H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. J. Natl. Cancer Inst. 102, 932–941 (2010).

    Google Scholar 

  40. Dalgliesh, G.L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010).

    Google Scholar 

  41. van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet. 41, 521–523 (2009).

    Google Scholar 

  42. Jones, S., et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010).

    Google Scholar 

  43. Wiegand, K.C., et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010).

    Google Scholar 

  44. Varela, I. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).

    Google Scholar 

  45. Fong, P.C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. J. Clin. Oncol. 28, 2512–2519 (2010).

    Google Scholar 

  46. Fong, P.C. et al. Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J. Clin. Oncol. 28, 2512–2519 (2010).

    Google Scholar 

  47. Mendes-Pereira, A.M. et al. Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol. Med. 1, 315–322 (2009).

    Google Scholar 

  48. McEllin, B. et al. PTEN loss compromises homologous recombination repair in astrocytes: implications for glioblastoma therapy with temozolomide or poly(ADP-ribose) polymerase inhibitors. Cancer Res. 70, 5457–5464 (2010).

    Google Scholar 

  49. Shen, W.H. et al. Essential role for nuclear PTEN in maintaining chromosomal integrity. Cell 128, 157–170 (2007).

    Google Scholar 

  50. The International Cancer Genome Consortium. International network of cancer genome projects. Nature 464, 993–998 (2010).

  51. Chen, Y. et al. Oncogenic mutations of ALK kinase in neuroblastoma. Nature 455, 971–974 (2008).

    Google Scholar 

  52. Janoueix-Lerosey, I. et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature 455, 967–970 (2008).

    Google Scholar 

  53. Soda, M. et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature 448, 561–566 (2007).

    Google Scholar 

  54. Tomlins, S.A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    Google Scholar 

  55. Chin, L. & Gray, J.W. Translating insights from the cancer genome into clinical practice. Nature 452, 553–563 (2008).

    Google Scholar 

  56. Verhaak, R.G.W. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).

    Google Scholar 

  57. Chin, L. et al. Essential role for oncogenic Ras in tumour maintenance. Nature 400, 468–472 (1999).

    Google Scholar 

  58. Kwong, L.N. & Chin, L. The brothers RAF. Cell 140, 180–182 (2010).

    Google Scholar 

  59. Shaw, A.T. et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J. Clin. Oncol. 27, 4247–4253 (2009).

    Google Scholar 

  60. Koivunen, J.P. et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin. Cancer Res. 14, 4275–4283 (2008).

    Google Scholar 

  61. Soda, M. et al. A mouse model for EML4-ALK-positive lung cancer. Proc. Natl. Acad. Sci. USA 105, 19893–19897 (2008).

    Google Scholar 

  62. McDermott, U. et al. Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors. Cancer Res. 68, 3389–3395 (2008).

    Google Scholar 

  63. Kwak, E.L. et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N. Engl. J. Med. 363, 1693–1703 (2010).

    Google Scholar 

  64. Dierks, C. et al. The ITK-SYK fusion oncogene induces a T-cell lymphoproliferative disease in mice mimicking human disease. Cancer Res. 70, 6193–6204 (2010).

    Google Scholar 

  65. Pechloff, K. et al. The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma. J. Exp. Med. 207, 1031–1044 (2010).

    Google Scholar 

  66. Riccaboni, M., Bianchi, I. & Petrillo, P. Spleen tyrosine kinases: biology, therapeutic targets and drugs. Drug Discov. Today 15, 517–530 (2010).

    Google Scholar 

  67. Uckun, F.M., Ek, R.O., Jan, S.T., Chen, C.L. & Qazi, S. Targeting SYK kinase-dependent anti-apoptotic resistance pathway in B-lineage acute lymphoblastic leukaemia (ALL) cells with a potent SYK inhibitory pentapeptide mimic. Br. J. Haematol. 149, 508–517 (2010).

    Google Scholar 

  68. Kwitkowski, V.E. et al. FDA approval summary: temsirolimus as treatment for advanced renal cell carcinoma. Oncologist 15, 428–435 (2010).

    Google Scholar 

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Authors and Affiliations

  1. Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

    Lynda Chin & Jannik N Andersen

  2. Department of Dermatology, Harvard Medical School, Boston, Massachusetts, USA

    Lynda Chin

  3. The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

    Lynda Chin

  4. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK

    P Andrew Futreal

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  1. Lynda Chin
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Correspondence to Lynda Chin.

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Chin, L., Andersen, J. & Futreal, P. Cancer genomics: from discovery science to personalized medicine. Nat Med 17, 297–303 (2011). https://doi.org/10.1038/nm.2323

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