Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Submitted on May 29, 2007
Accepted on October 1, 2007
The Genomic Landscapes of Human Breast and Colorectal Cancers
Laura D. Wood 1,D. Williams Parsons 1,Siân Jones 1,Jimmy Lin 1,Tobias Sjöblom 2,Rebecca J. Leary 1,Dong Shen 1,Simina M. Boca 3,Thomas Barber 4,Janine Ptak 1,Natalie Silliman 1,Steve Szabo 1,Zoltan Dezso 5,Vadim Ustyanksky 5,Tatiana Nikolskaya 6,Yuri Nikolsky 5,Rachel Karchin 7,Paul A. Wilson 7,Joshua S. Kaminker 8,Zemin Zhang 8,Randal Croshaw 9,Joseph Willis 10,Dawn Dawson 10,Michail Shipitsin 11,James K. V. Willson 12,Saraswati Sukumar 13,Kornelia Polyak 11,Ben Ho Park 13,Charit L. Pethiyagoda 14,P. V. Krishna Pant 14,Dennis G. Ballinger 14,Andrew B. Sparks 15,James Hartigan 16,Douglas R. Smith 16,Erick Suh 16,Nickolas Papadopoulos 1,Phillip Buckhaults 9,Sanford D. Markowitz 17,Giovanni Parmigiani 3*,Kenneth W. Kinzler 1*,Victor E. Velculescu 1*,Bert Vogelstein 1*
1 The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA. 2 The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.; Present address: Department of Genetics and Pathology, Uppsala University, SE-571 85 Uppsala, Sweden. 3 The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.; Departments of Bioinformatics and Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA. 4 The Ludwig Center for Cancer Genetics and Therapeutics and The Howard Hughes Medical Institute at The Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.; Present address: Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN 42685, USA. 5 GeneGo, Inc., St. Joseph, MI 49085, USA. 6 GeneGo, Inc., St. Joseph, MI 49085, USA.; Vavilov Institute of General Genetics, Moscow, Russia. 7 Department of Biomedical Engineering, Institute of Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. 8 Department of Bioinformatics, Genentech Inc., San Francisco, CA 94080, USA. 9 Department of Pathology and Microbiology, The Center for Colon Cancer Research, and The South Carolina Cancer Center, Division of Basic Research, The University of South Carolina, School of Medicine, Columbia, SC 29229, USA. 10 Department of Pathology and Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA. 11 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. 12 Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. 13 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. 14 Perlegen Sciences, Mountain View, CA 94043, USA. 15 Perlegen Sciences, Mountain View, CA 94043, USA.; Present address: Complete Genomics, Inc., Sunnyvale, CA 94085, USA. 16 Agencourt Bioscience Corporation, Beverly, MA 01915, USA. 17 Department of Medicine and Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, and Howard Hughes Medical Institute, Cleveland, OH 44106, USA.
* To whom correspondence should be addressed.
Giovanni Parmigiani , E-mail: gp{at}jhu.edu Kenneth W. Kinzler , E-mail: kinzlke{at}jhmi.edu Victor E. Velculescu , E-mail: velculescu{at}jhmi.edu Bert Vogelstein , E-mail: vogelbe{at}welch.jhu.edu
These authors contributed equally to this work.
Human cancer is caused by the accumulation of mutations in oncogenesand tumor suppressor genes. To catalogue the genetic changesthat occur during tumorigenesis, we isolated DNA from 11 breastand 11 colorectal tumors and determined the sequences of thegenes in the Reference Sequence database in these samples. Basedon analysis of exons representing 20,857 transcripts from 18,191genes, we conclude that the genomic landscapes of breast andcolorectal cancers are composed of a handful of commonly mutatedgene "mountains" and a much larger number of gene "hills" thatare mutated at low frequency. We describe statistical and bioinformatictools that may help identify mutations with a role in tumorigenesis.These results have implications for understanding the natureand heterogeneity of human cancers and for using personal genomicsfor tumor diagnosis and therapy.
The editors suggest the following Related Resources on Science sites:
In Science Magazine
PERSPECTIVES
Jeffrey M. Trent and Jeffrey W. Touchman (16 November 2007) Science318 (5853), 1079.
[DOI: 10.1126/science.1151428] |Summary »|Full Text »|PDF »
In Science Signaling
EDITORS' CHOICE
Paula A. Kiberstis (20 November 2007) Sci. STKE2007 (413), tw428.
[DOI: 10.1126/stke.4132007tw428] |Abstract »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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.
|Abstract »|Full Text »|PDF »
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 »
Tumorigenic activity and therapeutic inhibition of Rheb GTPase.
K. J. Mavrakis, H. Zhu, R. L.A. Silva, J. R. Mills, J. Teruya-Feldstein, S. W. Lowe, W. Tam, J. Pelletier, and H.-G. Wendel (2008)
Genes & Dev.
22, 2178-2188
|Abstract »|Full Text »|PDF »
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
|Abstract »|Full Text »|PDF »
A comprehensive assay for targeted multiplex amplification of human DNA sequences.
S. Krishnakumar, J. Zheng, J. Wilhelmy, M. Faham, M. Mindrinos, and R. Davis (2008)
PNAS
105, 9296-9301
|Abstract »|Full Text »|PDF »
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 »
BRAFV600E Mutation Is Associated with Preferential Sensitivity to Mitogen-Activated Protein Kinase Kinase Inhibition in Thyroid Cancer Cell Lines.
R. Leboeuf, J. E. Baumgartner, M. Benezra, R. Malaguarnera, D. Solit, C. A. Pratilas, N. Rosen, J. A. Knauf, and J. A. Fagin (2008)
J. Clin. Endocrinol. Metab.
93, 2194-2201
|Abstract »|Full Text »|PDF »
Mechanisms of malignant progression.
R. A. Weinberg (2008)
Carcinogenesis
29, 1092-1095
|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 »
More Controversy than Ever - Challenges and Promises Towards Personalized Treatment of Gastric Cancer.
T. Liakakos and D. H. Roukos (2008)
Ann. Surg. Oncol.
15, 956-960
|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 »
An Oncogene-Induced DNA Damage Model for Cancer Development.
T. D. Halazonetis, V. G. Gorgoulis, and J. Bartek (2008)
Science
319, 1352-1355
|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 »
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 »
Commentary: Novel Therapies for Cancer: Why Dirty Might Be Better.
Cell growth, global phosphotyrosine elevation, and c-Met phosphorylation through Src family kinases in colorectal cancer cells.
M. Emaduddin, D. C. Bicknell, W. F. Bodmer, and S. M. Feller (2008)
PNAS
105, 2358-2362
|Abstract »|Full Text »|PDF »
Improving Outcomes for Patients With Hormone Receptor-Positive Breast Cancer: Back to the Drawing Board.
M. J. Ellis (2008)
J Natl Cancer Inst
100, 159-161
|Full Text »|PDF »
Cancer Proliferation Gene Discovery Through Functional Genomics.
M. R. Schlabach, J. Luo, N. L. Solimini, G. Hu, Q. Xu, M. Z. Li, Z. Zhao, A. Smogorzewska, M. E. Sowa, X. L. Ang, et al. (2008)
Science
319, 620-624
|Abstract »|Full Text »|PDF »
Cancer Genes Complexity Clarified and Multiplied.
(2008)
Journal Watch Dermatology
2008, 2
|Full Text »
,
