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,¹ Dong Shen,¹ Simina M. Boca,^1,2 Thomas Barber,¹ Janine Ptak,¹ Natalie Silliman,¹ Steve Szabo,¹ Zoltan Dezso,³ Vadim Ustyanksky,³ Tatiana Nikolskaya,^3,4 Yuri Nikolsky,³ Rachel Karchin,⁵ Paul A. Wilson,⁵ Joshua S. Kaminker,⁶ Zemin Zhang,⁶ Randal Croshaw,⁷ Joseph Willis,⁸ Dawn Dawson,⁸ Michail Shipitsin,⁹ James K. V. Willson,¹⁰ Saraswati Sukumar,¹¹ Kornelia Polyak,⁹ Ben Ho Park,¹¹ Charit L. Pethiyagoda,¹² P. V. Krishna Pant,¹² Dennis G. Ballinger,¹² Andrew B. Sparks,¹² James Hartigan,¹³ Douglas R. Smith,¹³ Erick Suh,¹³ Nickolas Papadopoulos,¹ Phillip Buckhaults,⁷ Sanford D. Markowitz,¹⁴ Giovanni Parmigiani,^1|| Kenneth W. Kinzler,^1|| Victor E. Velculescu,^1|| Bert Vogelstein^1||

Abstract: Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for 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, Uppsala University, 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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Nucleic Acids Res. 40, D978-D983
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RAD51 can inhibit PDGF-B-induced gliomagenesis and genomic instability.

U. K. Westermark, N. Lindberg, P. Roswall, D. Brasater, H. R. Helgadottir, S.-M. Hede, A. Zetterberg, M. Jasin, M. Nister, and L. Uhrbom (2011)
Neuro Oncology 13, 1277-1287
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Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers.

M. H. Abdel-Rahman, R. Pilarski, C. M. Cebulla, J. B. Massengill, B. N. Christopher, G. Boru, P. Hovland, and F. H. Davidorf (2011)
J. Med. Genet. 48, 856-859
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Relationship between Quantitative GRB7 RNA Expression and Recurrence after Adjuvant Anthracycline Chemotherapy in Triple-Negative Breast Cancer.

J. A. Sparano, L. J. Goldstein, B. H. Childs, S. Shak, D. Brassard, S. Badve, F. L. Baehner, R. Bugarini, S. Rowley, E. A. Perez, et al. (2011)
Clin. Cancer Res. 17, 7194-7203
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Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide.

Y. X. Zhu, E. Braggio, C.-X. Shi, L. A. Bruins, J. E. Schmidt, S. Van Wier, X.-B. Chang, C. C. Bjorklund, R. Fonseca, P. L. Bergsagel, et al. (2011)
Blood 118, 4771-4779
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A Molecularly Annotated Platform of Patient-Derived Xenografts ("Xenopatients") Identifies HER2 as an Effective Therapeutic Target in Cetuximab-Resistant Colorectal Cancer.

A. Bertotti, G. Migliardi, F. Galimi, F. Sassi, D. Torti, C. Isella, D. Cora, F. Di Nicolantonio, M. Buscarino, C. Petti, et al. (2011)
Cancer Discovery 1, 508-523
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ZNF668 Functions as a Tumor Suppressor by Regulating p53 Stability and Function in Breast Cancer.

R. Hu, G. Peng, H. Dai, E.-K. Breuer, K. Stemke-Hale, K. Li, A. M. Gonzalez-Angulo, G. B. Mills, and S.-Y. Lin (2011)
Cancer Res. 71, 6524-6534
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Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers.

A. Kumar, T. A. White, A. P. MacKenzie, N. Clegg, C. Lee, R. F. Dumpit, I. Coleman, S. B. Ng, S. J. Salipante, M. J. Rieder, et al. (2011)
PNAS 108, 17087-17092
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Genome-wide Methylation Analysis Identifies Genes Specific to Breast Cancer Hormone Receptor Status and Risk of Recurrence.

M. J. Fackler, C. B. Umbricht, D. Williams, P. Argani, L.-A. Cruz, V. F. Merino, W. W. Teo, Z. Zhang, P. Huang, K. Visvananthan, et al. (2011)
Cancer Res. 71, 6195-6207
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C/EBP{alpha}, C/EBP{alpha} Oncoproteins, or C/EBP{beta} Preferentially Bind NF-{kappa}B p50 Compared with p65, Focusing Therapeutic Targeting on the C/EBP:p50 Interaction.

J. E. Dooher, I. Paz-Priel, S. Houng, A. S. Baldwin Jr, and A. D. Friedman (2011)
Mol. Cancer Res. 9, 1395-1405
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ERK1/2 and p38{alpha}/{beta} Signaling in Tumor Cell Quiescence: Opportunities to Control Dormant Residual Disease.

M. S. Sosa, A. Avivar-Valderas, P. Bragado, H.-C. Wen, and J. A. Aguirre-Ghiso (2011)
Clin. Cancer Res. 17, 5850-5857
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Mutations in CIC and FUBP1 Contribute to Human Oligodendroglioma.

C. Bettegowda, N. Agrawal, Y. Jiao, M. Sausen, L. D. Wood, R. H. Hruban, F. J. Rodriguez, D. P. Cahill, R. McLendon, G. Riggins, et al. (2011)
Science 333, 1453-1455
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