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The Consensus Coding Sequences of Human Breast and Colorectal Cancers
Tobias Sjöblom,1*Siân Jones,1*Laura D. Wood,1*D. Williams Parsons,1*Jimmy Lin,1Thomas D. Barber,1Diana Mandelker,1Rebecca J. Leary,1Janine Ptak,1Natalie Silliman,1Steve Szabo,1Phillip Buckhaults,2Christopher Farrell,2Paul Meeh,2Sanford D. Markowitz,3Joseph Willis,4Dawn Dawson,4James K. V. Willson,5Adi F. Gazdar,6James Hartigan,7Leo Wu,8Changsheng Liu,8Giovanni Parmigiani,9Ben Ho Park,10Kurtis E. Bachman,11Nickolas Papadopoulos,1Bert Vogelstein,1Kenneth W. Kinzler,1Victor E. Velculescu1
The elucidation of the human genome sequence has made it possibleto identify genetic alterations in cancers in unprecedenteddetail. To begin a systematic analysis of such alterations,we determined the sequence of well-annotated human protein-codinggenes in two common tumor types. Analysis of 13,023 genes in11 breast and 11 colorectal cancers revealed that individualtumors accumulate an average of 90 mutant genes but that onlya subset of these contribute to the neoplastic process. Usingstringent criteria to delineate this subset, we identified 189genes (average of 11 per tumor) that were mutated at significantfrequency. The vast majority of these genes were not known tobe genetically altered in tumors and are predicted to affecta wide range of cellular functions, including transcription,adhesion, and invasion. These data define the genetic landscapeof two human cancer types, provide new targets for diagnosticand therapeutic intervention, and open fertile avenues for basicresearch in tumor biology.
1 Ludwig Center and Howard Hughes Medical Institute, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. 2 Department of Pathology and Microbiology, Center for Colon Cancer Research, and South Carolina Cancer Center, Division of Basic Research, University of South Carolina School of Medicine, Columbia, SC 29229, USA. 3 Department of Medicine, Ireland Cancer Center, and Howard Hughes Medical Institute, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA. 4 Department of Pathology and Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA. 5 Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 6 Hamon Center for Therapeutic Oncology Research and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. 7 Agencourt Bioscience Corporation, Beverly, MA 01915, USA. 8 Soft Genetics LLC, State College, PA 16803, USA. 9 Departments of Oncology, Biostatistics, and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA. 10 Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. 11 Department of Radiation Oncology and Department of Biochemistry and Molecular Biology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
* These authors contributed equally to this work.
Present address: Lilly Research Laboratories, Eli Lilly andCompany, Indianapolis, IN 46285, USA.
To whom correspondence should be addressed. E-mail: vogelbe{at}jhmi.edu (B.V.); kinzlke{at}jhmi.edu (K.W.K.); velculescu{at}jhmi.edu (V.E.V.)
Gad Getz, Holger Höfling, Jill P. Mesirov, Todd R. Golub, Matthew Meyerson, Robert Tibshirani, and Eric S. Lander (14 September 2007) Science317 (5844), 1500b.
[DOI: 10.1126/science.1138764] |Abstract »|Full Text »|PDF »|Supporting Online Material »
Giovanni Parmigiani, Jimmy Lin, Simina M. Boca, Tobias Sjöblom, Siân Jones, Laura D. Wood, D. Williams Parsons, Thomas Barber, Phillip Buckhaults, Sanford D. Markowitz, Ben Ho Park, Kurtis E. Bachman, Nickolas Papadopoulos, Bert Vogelstein, Kenneth W. Kinzler, and Victor E. Velculescu (14 September 2007) Science317 (5844), 1500d.
[DOI: 10.1126/science.1138773] |Abstract »|Full Text »|PDF »|Supporting Online Material »
LETTERS
Wee J. Chng;, Lawrence A. Loeb, Jason H. Bielas;, Bernard S. Strauss;, Tobias Sjöblom, Siân Jones, Laura D. Wood, D. Williams Parsons, Jimmy Lin, Thomas Barber, Diana Mandelker, Rebecca J. Leary, Janine Ptak, Natalie Silliman, Steve Szabo, Phillip Buckhaults, Christopher Farrell, Paul Meeh, Sanford D. Markowitz, Joseph Willis, Dawn Dawson, James K V. Willson, Adi F. Gazdar, James Hartigan, Leo Wu, Changsheng Liu, Giovanni Parmigiani, Ben Ho Park, Kurtis E. Bachman, Nickolas Papadopoulos, Bert Vogelstein, Kenneth W. Kinzler, and Victor E. Velculescu (9 February 2007) Science315 (5813), 762b.
[DOI: 10.1126/science.315.5813.762b] |Full Text »|PDF »
NEWS OF THE WEEK
Jocelyn Kaiser (8 September 2006) Science313 (5792), 1370.
[DOI: 10.1126/science.313.5792.1370] |Summary »|Full Text »|PDF »
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18, 751-762
|Abstract »|Full Text »|PDF »
The rexinoid LG100268 and the synthetic triterpenoid CDDO-methyl amide are more potent than erlotinib for prevention of mouse lung carcinogenesis.
K. Liby, C. C. Black, D. B. Royce, C. R. Williams, R. Risingsong, M. M. Yore, X. Liu, T. Honda, G. W. Gribble, W. W. Lamph, et al. (2008)
Mol. Cancer Ther.
7, 1251-1257
|Abstract »|Full Text »|PDF »
High-throughput sequence analysis of the tyrosine kinome in acute myeloid leukemia.
M. M. Loriaux, R. L. Levine, J. W. Tyner, S. Frohling, C. Scholl, E. P. Stoffregen, G. Wernig, H. Erickson, C. A. Eide, R. Berger, et al. (2008)
Blood
111, 4788-4796
|Abstract »|Full Text »|PDF »
Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia.
M. H. Tomasson, Z. Xiang, R. Walgren, Y. Zhao, Y. Kasai, T. Miner, R. E. Ries, O. Lubman, D. H. Fremont, M. D. McLellan, et al. (2008)
Blood
111, 4797-4808
|Abstract »|Full Text »|PDF »
Mutations in the neutral sphingomyelinase gene SMPD3 implicate the ceramide pathway in human leukemias.
W. J. Kim, R. A. Okimoto, L. E. Purton, M. Goodwin, S. M. Haserlat, F. Dayyani, D. A. Sweetser, A. I. McClatchey, O. A. Bernard, A. T. Look, et al. (2008)
Blood
111, 4716-4722
|Abstract »|Full Text »|PDF »
A Role for TAZ in Migration, Invasion, and Tumorigenesis of Breast Cancer Cells.
S. W. Chan, C. J. Lim, K. Guo, C. P. Ng, I. Lee, W. Hunziker, Q. Zeng, and W. Hong (2008)
Cancer Res.
68, 2592-2598
|Abstract »|Full Text »|PDF »
Genome-Wide Promoter Analysis Uncovers Portions of the Cancer Methylome.
M. O. Hoque, M. S. Kim, K. L. Ostrow, J. Liu, G. B. A. Wisman, H. L. Park, M. L. Poeta, C. Jeronimo, R. Henrique, A. Lendvai, et al. (2008)
Cancer Res.
68, 2661-2670
|Abstract »|Full Text »|PDF »
A. Jimeno, A. C. Tan, J. Coffa, N.V. Rajeshkumar, P. Kulesza, B. Rubio-Viqueira, J. Wheelhouse, B. Diosdado, W. A. Messersmith, C. Iacobuzio-Donahue, et al. (2008)
Cancer Res.
68, 2841-2849
|Abstract »|Full Text »|PDF »
Identification of p18INK4c as a Tumor Suppressor Gene in Glioblastoma Multiforme.
D. A. Solomon, J.-S. Kim, S. Jenkins, H. Ressom, M. Huang, N. Coppa, L. Mabanta, D. Bigner, H. Yan, W. Jean, et al. (2008)
Cancer Res.
68, 2564-2569
|Abstract »|Full Text »|PDF »
Eph, a Protein Family Coming of Age: More Confusion, Insight, or Complexity?.
Evidence for Editing of Human Papillomavirus DNA by APOBEC3 in Benign and Precancerous Lesions.
J.-P. Vartanian, D. Guetard, M. Henry, and S. Wain-Hobson (2008)
Science
320, 230-233
|Abstract »|Full Text »|PDF »
Single-Molecule DNA Sequencing of a Viral Genome.
T. D. Harris, P. R. Buzby, H. Babcock, E. Beer, J. Bowers, I. Braslavsky, M. Causey, J. Colonell, J. DiMeo, J. W. Efcavitch, et al. (2008)
Science
320, 106-109
|Abstract »|Full Text »|PDF »
Comparative lesion sequencing provides insights into tumor evolution.
S. Jones, W.-d. Chen, G. Parmigiani, F. Diehl, N. Beerenwinkel, T. Antal, A. Traulsen, M. A. Nowak, C. Siegel, V. E. Velculescu, et al. (2008)
PNAS
105, 4283-4288
|Abstract »|Full Text »|PDF »
Promoter Methylation of Genes in and around the Candidate Lung Cancer Susceptibility Locus 6q23-25.
M. Tessema, R. Willink, K. Do, Y. Y. Yu, W. Yu, E. O. Machida, M. Brock, L. Van Neste, C. A. Stidley, S. B. Baylin, et al. (2008)
Cancer Res.
68, 1707-1714
|Abstract »|Full Text »|PDF »
Chromatid cohesion defects may underlie chromosome instability in human colorectal cancers.
T. D. Barber, K. McManus, K. W. Y. Yuen, M. Reis, G. Parmigiani, D. Shen, I. Barrett, Y. Nouhi, F. Spencer, S. Markowitz, et al. (2008)
PNAS
105, 3443-3448
|Abstract »|Full Text »|PDF »
Transcriptome sequencing of malignant pleural mesothelioma tumors.
D. J. Sugarbaker, W. G. Richards, G. J. Gordon, L. Dong, A. De Rienzo, G. Maulik, J. N. Glickman, L. R. Chirieac, M.-L. Hartman, B. E. Taillon, et al. (2008)
PNAS
105, 3521-3526
|Abstract »|Full Text »|PDF »
Clonal Selection in Malignant Transformation of Human Fibroblasts Transduced with Defined Cellular Oncogenes.
A. M. Mahale, Z. A.T. Khan, M. Igarashi, G. J. Nanjangud, R. F. Qiao, S. Yao, S. W. Lee, and S. A. Aaronson (2008)
Cancer Res.
68, 1417-1426
|Abstract »|Full Text »|PDF »
Epigenetic inactivation of protein kinase D1 in gastric cancer and its role in gastric cancer cell migration and invasion.
M. Kim, H.-R. Jang, J.-H. Kim, S.-M. Noh, K.-S. Song, J.-S. Cho, H.-Y. Jeong, J. C. Norman, P. T. Caswell, G. H. Kang, et al. (2008)
Carcinogenesis
29, 629-637
|Abstract »|Full Text »|PDF »
90 mutant genes but that only a subset of these contribute to the neoplastic process. Using stringent criteria to delineate this subset, we identified 189 genes (average of 11 per tumor) that were mutated at significant frequency. The vast majority of these genes were not known to be genetically altered in tumors and are predicted to affect a wide range of cellular functions, including transcription, adhesion, and invasion. These data define the genetic landscape of two human cancer types, provide new targets for diagnostic and therapeutic intervention, and open fertile avenues for basic research in tumor biology. 
Present address: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. 
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