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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,1*Rebecca J. Leary,1Dong Shen,1Simina M. Boca,1,2Thomas Barber,1Janine Ptak,1Natalie Silliman,1Steve Szabo,1Zoltan Dezso,3Vadim Ustyanksky,3Tatiana Nikolskaya,3,4Yuri Nikolsky,3Rachel Karchin,5Paul A. Wilson,5Joshua S. Kaminker,6Zemin Zhang,6Randal Croshaw,7Joseph Willis,8Dawn Dawson,8Michail Shipitsin,9James K. V. Willson,10Saraswati Sukumar,11Kornelia Polyak,9Ben Ho Park,11Charit L. Pethiyagoda,12P. V. Krishna Pant,12Dennis G. Ballinger,12Andrew B. Sparks,12James Hartigan,13Douglas R. Smith,13Erick Suh,13Nickolas Papadopoulos,1Phillip Buckhaults,7Sanford D. Markowitz,14Giovanni Parmigiani,1||Kenneth W. Kinzler,1||Victor E. Velculescu,1||Bert Vogelstein1||
Human cancer is caused by the accumulation of mutations in oncogenesand tumor suppressor genes. To catalog the genetic changes thatoccur during tumorigenesis, we isolated DNA from 11 breast and11 colorectal tumors and determined the sequences of the genesin the Reference Sequence database in these samples. Based onanalysis 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.
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 Department of Biostatistics, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA. 3 GeneGo, St. Joseph, MI 49085, USA. 4 Vavilov Institute of General Genetics, Moscow, Russia. 5 Department of Biomedical Engineering, Institute of Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA. 6 Department of Bioinformatics, Genentech, San Francisco, CA 94080, USA. 7 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. 8 Department of Pathology and Ireland Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA. 9 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. 10 Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA. 11 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231, USA. 12 Perlegen Sciences, Mountain View, CA 94043, USA. 13 Agencourt Bioscience Corporation, Beverly, MA 01915, USA. 14 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.
* These authors contributed equally to this work.
Present address: Department of Genetics and Pathology, UppsalaUniversity, SE-751 85 Uppsala, Sweden.
Present address: Lilly Research Labs, Eli Lilly and Company,Indianapolis, IN 42685, USA.
Present address: Complete Genomics, Sunnyvale, CA 94085, USA.
|| To whom correspondence should be addressed. E-mail: gp{at}jhu.edu (G.P.); kinzlke{at}jhmi.edu (K.W.K.); velculescu{at}jhmi.edu (V.E.V.); vogelbe{at}welch.jhu.edu (B.V.)
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