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Originally published in Science Express on 7 September 2006
Science 13 October 2006:
Vol. 314. no. 5797, pp. 268 - 274
DOI: 10.1126/science.1133427
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Research Articles

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,1 Thomas D. Barber,1{dagger} Diana Mandelker,1 Rebecca J. Leary,1 Janine Ptak,1 Natalie Silliman,1 Steve Szabo,1 Phillip Buckhaults,2 Christopher Farrell,2 Paul Meeh,2 Sanford D. Markowitz,3 Joseph Willis,4 Dawn Dawson,4 James K. V. Willson,5 Adi F. Gazdar,6 James Hartigan,7 Leo Wu,8 Changsheng Liu,8 Giovanni Parmigiani,9 Ben Ho Park,10 Kurtis E. Bachman,11 Nickolas Papadopoulos,1 Bert Vogelstein,1{ddagger} Kenneth W. Kinzler,1{ddagger} Victor E. Velculescu1{ddagger}

The elucidation of the human genome sequence has made it possible to identify genetic alterations in cancers in unprecedented detail. To begin a systematic analysis of such alterations, we determined the sequence of well-annotated human protein-coding genes in two common tumor types. Analysis of 13,023 genes in 11 breast and 11 colorectal cancers revealed that individual tumors accumulate an average of ~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.

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.

{dagger} Present address: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.

{ddagger} 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.)

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Nested Patch PCR enables highly multiplexed mutation discovery in candidate genes.
K. E. Varley and R. D. Mitra (2008)
Genome Res. 18, 1844-1850
   Abstract »    Full Text »    PDF »
Integrated analysis of homozygous deletions, focal amplifications, and sequence alterations in breast and colorectal cancers.
R. J. Leary, J. C. Lin, J. Cummins, S. Boca, L. D. Wood, D. W. Parsons, S. Jones, T. Sjoblom, B.-H. Park, R. Parsons, et al. (2008)
PNAS 105, 16224-16229
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Deletion of Mtg16, a Target of t(16;21), Alters Hematopoietic Progenitor Cell Proliferation and Lineage Allocation.
B. J. Chyla, I. Moreno-Miralles, M. A. Steapleton, M. A. Thompson, S. Bhaskara, M. Engel, and S. W. Hiebert (2008)
Mol. Cell. Biol. 28, 6234-6247
   Abstract »    Full Text »    PDF »
RNAi-Mediated Silencing of Nuclear Factor Erythroid-2-Related Factor 2 Gene Expression in Non-Small Cell Lung Cancer Inhibits Tumor Growth and Increases Efficacy of Chemotherapy.
A. Singh, S. Boldin-Adamsky, R. K. Thimmulappa, S. K. Rath, H. Ashush, J. Coulter, A. Blackford, S. N. Goodman, F. Bunz, W. H. Watson, et al. (2008)
Cancer Res. 68, 7975-7984
   Abstract »    Full Text »    PDF »
Functional Analysis of a Cell Cycle-Associated, Tumor-Suppressive Gene, Protein Tyrosine Phosphatase Receptor Type G, in Nasopharyngeal Carcinoma.
A. K. L. Cheung, H. L. Lung, S. C. Hung, E. W. L. Law, Y. Cheng, W. L. Yau, D. K. Bangarusamy, L. D. Miller, E. T.-B. Liu, J.-Y. Shao, et al. (2008)
Cancer Res. 68, 8137-8145
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Prioritization of candidate cancer genes--an aid to oncogenomic studies.
S. J. Furney, B. Calvo, P. Larranaga, J. A. Lozano, and N. Lopez-Bigas (2008)
Nucleic Acids Res. 36, e115
   Abstract »    Full Text »    PDF »
Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses.
S. Jones, X. Zhang, D. W. Parsons, J. C.-H. Lin, R. J. Leary, P. Angenendt, P. Mankoo, H. Carter, H. Kamiyama, A. Jimeno, et al. (2008)
Science 321, 1801-1806
   Abstract »    Full Text »    PDF »
An Integrated Genomic Analysis of Human Glioblastoma Multiforme.
D. W. Parsons, S. Jones, X. Zhang, J. C.-H. Lin, R. J. Leary, P. Angenendt, P. Mankoo, H. Carter, I-M. Siu, G. L. Gallia, et al. (2008)
Science 321, 1807-1812
   Abstract »    Full Text »    PDF »
Germline Allele-Specific Expression of TGFBR1 Confers an Increased Risk of Colorectal Cancer.
L. Valle, T. Serena-Acedo, S. Liyanarachchi, H. Hampel, I. Comeras, Z. Li, Q. Zeng, H.-T. Zhang, M. J. Pennison, M. Sadim, et al. (2008)
Science 321, 1361-1365
   Abstract »    Full Text »    PDF »
Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing.
P. J. Campbell, E. D. Pleasance, P. J. Stephens, E. Dicks, R. Rance, I. Goodhead, G. A. Follows, A. R. Green, P. A. Futreal, and M. R. Stratton (2008)
PNAS 105, 13081-13086
   Abstract »    Full Text »    PDF »
Advances in Chemical Carcinogenesis: A Historical Review and Prospective.
L. A. Loeb and C. C. Harris (2008)
Cancer Res. 68, 6863-6872
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A Novel Acetylenic Tricyclic bis-(Cyano Enone) Potently Induces Phase 2 Cytoprotective Pathways and Blocks Liver Carcinogenesis Induced by Aflatoxin.
K. Liby, M. M. Yore, B. D. Roebuck, K. J. Baumgartner, T. Honda, C. Sundararajan, H. Yoshizawa, G. W. Gribble, C. R. Williams, R. Risingsong, et al. (2008)
Cancer Res. 68, 6727-6733
   Abstract »    Full Text »    PDF »
Gain and loss of phosphorylation sites in human cancer.
P. Radivojac, P. H. Baenziger, M. G. Kann, M. E. Mort, M. W. Hahn, and S. D. Mooney (2008)
Bioinformatics 24, i241-i247
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An Integrative Genomic and Proteomic Analysis of PIK3CA, PTEN, and AKT Mutations in Breast Cancer.
K. Stemke-Hale, A. M. Gonzalez-Angulo, A. Lluch, R. M. Neve, W.-L. Kuo, M. Davies, M. Carey, Z. Hu, Y. Guan, A. Sahin, et al. (2008)
Cancer Res. 68, 6084-6091
   Abstract »    Full Text »    PDF »
Tilting at Quixotic Trait Loci (QTL): An Evolutionary Perspective on Genetic Causation.
K. M. Weiss (2008)
Genetics 179, 1741-1756
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Elevated protein tyrosine phosphatase activity provokes Eph/ephrin-facilitated adhesion of pre-B leukemia cells.
S. H. Wimmer-Kleikamp, E. Nievergall, K. Gegenbauer, S. Adikari, M. Mansour, T. Yeadon, A. W. Boyd, N. R. Patani, and M. Lackmann (2008)
Blood 112, 721-732
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Cell Competition and Its Possible Relation to Cancer.
N. E. Baker and W. Li (2008)
Cancer Res. 68, 5505-5507
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A genome-wide RNAi screen for Wnt/{beta}-catenin pathway components identifies unexpected roles for TCF transcription factors in cancer.
W. Tang, M. Dodge, D. Gundapaneni, C. Michnoff, M. Roth, and L. Lum (2008)
PNAS 105, 9697-9702
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A Syngeneic Variance Library for Functional Annotation of Human Variation: Application to BRCA2.
T. Hucl, C. Rago, E. Gallmeier, J. R. Brody, M. Gorospe, and S. E. Kern (2008)
Cancer Res. 68, 5023-5030
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The complement protein properdin binds apoptotic T cells and promotes complement activation and phagocytosis.
C. Kemper, L. M. Mitchell, L. Zhang, and D. E. Hourcade (2008)
PNAS 105, 9023-9028
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Epigenetic Signatures of Familial Cancer Are Characteristic of Tumor Type and Family Category.
E. I. Joensuu, W. M. Abdel-Rahman, M. Ollikainen, S. Ruosaari, S. Knuutila, and P. Peltomaki (2008)
Cancer Res. 68, 4597-4605
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The Previously Undescribed ZKSCAN3 (ZNF306) Is a Novel "Driver" of Colorectal Cancer Progression.
L. Yang, S. R. Hamilton, A. Sood, T. Kuwai, L. Ellis, A. Sanguino, G. Lopez-Berestein, and D. D. Boyd (2008)
Cancer Res. 68, 4321-4330
   Abstract »    Full Text »    PDF »
Defining the blueprint of the cancer genome.
V. E. Velculescu (2008)
Carcinogenesis 29, 1087-1091
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