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.

Published Online September 4, 2008
Science DOI: 10.1126/science.1164368

Research Articles

Submitted on August 7, 2008
Accepted on August 27, 2008

Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses

Siân Jones 1{dagger}, Xiaosong Zhang 1{dagger}, D. Williams Parsons 2{dagger}, Jimmy Cheng-Ho Lin 1{dagger}, Rebecca J. Leary 1{dagger}, Philipp Angenendt 1{dagger}, Parminder Mankoo 3, Hannah Carter 3, Hirohiko Kamiyama 4, Antonio Jimeno 1, Seung-Mo Hong 4, Baojin Fu 4, Ming-Tseh Lin 4, Eric S. Calhoun 1, Mihoko Kamiyama 4, Kimberly Walter 4, Tatiana Nikolskaya 5, Yuri Nikolsky 6, James Hartigan 7, Douglas R. Smith 7, Manuel Hidalgo 1, Steven D. Leach 8, Alison P. Klein 9, Elizabeth M. Jaffee 9, Michael Goggins 9, Anirban Maitra 9, Christine Iacobuzio-Donahue 9, James R. Eshleman 9, Scott E. Kern 9, Ralph H. Hruban 9, Rachel Karchin 3, Nickolas Papadopoulos 1, Giovanni Parmigiani 10, Bert Vogelstein 1*, Victor E. Velculescu 1*, Kenneth W. Kinzler 1*

1 The Sol Goldman Pancreatic Cancer Research Center, The Ludwig Center and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
2 The Sol Goldman Pancreatic Cancer Research Center, The Ludwig Center and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.; Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Houston TX 77030, USA.
3 Department of Biomedical Engineering, Institute of Computational Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21218, USA.
4 Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
5 Vavilov Institute for General Genetics, Moscow B333, 117809, Russia.
6 GeneGo, Inc., St. Joseph, MI 49085, USA.
7 Agencourt Bioscience Corporation, Beverly, MA 01915, USA.
8 The Sol Goldman Pancreatic Cancer Research Center, The Ludwig Center and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.; Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
9 The Sol Goldman Pancreatic Cancer Research Center, The Ludwig Center and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
10 The Sol Goldman Pancreatic Cancer Research Center, The Ludwig Center and The Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.; Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.

* To whom correspondence should be addressed.
Bert Vogelstein , E-mail: bertvog{at}gmail.com
Victor E. Velculescu , E-mail: velculescu{at}jhmi.edu
Kenneth W. Kinzler , E-mail: kinzlke{at}welch.jhu.edu

{dagger}These authors contributed equally to this work.

There are currently few therapeutic options for patients with pancreatic cancer, and new insights into the pathogenesis of this lethal disease are urgently needed. Towards this end, we performed a comprehensive genetic analysis of 24 pancreatic cancers. We first determined the sequences of 23,219 transcripts, representing 20,661 protein-coding genes, in these samples. Then, we searched for homozygous deletions and amplifications in the tumor DNA by using microarrays containing probes for ~106 single nucleotide polymorphisms (SNPs). We found that pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations. These alterations defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67% to 100% of the tumors. Analysis of these tumors' transcriptomes with next-generation sequencing-by-synthesis technologies provided independent evidence for the significance of these pathways and processes. Our data indicate that genetically altered core pathways and regulatory processes only become evident once the coding regions of the genome are analyzed in depth. Dysregulation of these core pathways and processes through mutation can explain the major features of pancreatic tumorigenesis.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Personalized Cancer Therapy With Selective Kinase Inhibitors: An Emerging Paradigm in Medical Oncology.
U. McDermott and J. Settleman (2009)
J. Clin. Oncol. 27, 5650-5659
   Abstract »    Full Text »    PDF »
The Hedgehog Pathway and Pancreatic Cancer.
M. Hidalgo and A. Maitra (2009)
N. Engl. J. Med. 361, 2094-2096
   Full Text »    PDF »
Network of Cancer Genes: a web resource to analyze duplicability, orthology and network properties of cancer genes.
A. S. Syed, M. D'Antonio, and F. D. Ciccarelli (2009)
Nucleic Acids Res.
   Abstract »    Full Text »    PDF »
Characterization of Novel Diaryl Oxazole-Based Compounds as Potential Agents to Treat Pancreatic Cancer.
A. Y. Shaw, M. C. Henderson, G. Flynn, B. Samulitis, H. Han, S. P. Stratton, H.-H. S. Chow, L. H. Hurley, and R. T. Dorr (2009)
J. Pharmacol. Exp. Ther. 331, 636-647
   Abstract »    Full Text »    PDF »
Resequencing and copy number analysis of the human tyrosine kinase gene family in poorly differentiated gastric cancer.
T. Kubo, Y. Kuroda, H. Shimizu, A. Kokubu, N. Okada, F. Hosoda, Y. Arai, Y. Nakamura, H. Taniguchi, K. Yanagihara, et al. (2009)
Carcinogenesis 30, 1857-1864
   Abstract »    Full Text »    PDF »
Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer.
M. L. Sos, S. Fischer, R. Ullrich, M. Peifer, J. M. Heuckmann, M. Koker, S. Heynck, I. Stuckrath, J. Weiss, F. Fischer, et al. (2009)
PNAS 106, 18351-18356
   Abstract »    Full Text »    PDF »
A Modified Sleeping Beauty Transposon System That Can Be Used to Model a Wide Variety of Human Cancers in Mice.
A. J. Dupuy, L. M. Rogers, J. Kim, K. Nannapaneni, T. K. Starr, P. Liu, D. A. Largaespada, T. E. Scheetz, N. A. Jenkins, and N. G. Copeland (2009)
Cancer Res. 69, 8150-8156
   Abstract »    Full Text »    PDF »
Screening for familial pancreatic cancer: is doing something better than doing nothing?.
R. E Brand (2009)
Gut 58, 1321-1322
   Full Text »    PDF »
Calcium Pumps in Health and Disease.
M. Brini and E. Carafoli (2009)
Physiol Rev 89, 1341-1378
   Abstract »    Full Text »    PDF »
Microarray analysis of cytoplasmic versus whole cell RNA reveals a considerable number of missed and false positive mRNAs.
H. W. Trask, R. Cowper-Sal-lari, M. A. Sartor, J. Gui, C. V. Heath, J. Renuka, A.-J. Higgins, P. Andrews, M. Korc, J. H. Moore, et al. (2009)
RNA 15, 1917-1928
   Abstract »    Full Text »    PDF »
MYC Activity Mitigates Response to Rapamycin in Prostate Cancer through Eukaryotic Initiation Factor 4E-Binding Protein 1-Mediated Inhibition of Autophagy.
B. S. Balakumaran, A. Porrello, D. S. Hsu, W. Glover, A. Foye, J. Y. Leung, B. A. Sullivan, W. C. Hahn, M. Loda, and P. G. Febbo (2009)
Cancer Res. 69, 7803-7810
   Abstract »    Full Text »    PDF »
Tumor markers in pancreatic cancer: a European Group on Tumor Markers (EGTM) status report.
M. J. Duffy, C. Sturgeon, R. Lamerz, C. Haglund, V. L. Holubec, R. Klapdor, A. Nicolini, O. Topolcan, and V. Heinemann (2009)
Ann. Onc.
   Abstract »    Full Text »    PDF »
Serum Fatty Acid Synthase as a Marker of Pancreatic Neoplasia.
K. Walter, S.-M. Hong, S. Nyhan, M. Canto, N. Fedarko, A. Klein, M. Griffith, N. Omura, S. Medghalchi, F. Kuhajda, et al. (2009)
Cancer Epidemiol. Biomarkers Prev. 18, 2380-2385
   Abstract »    Full Text »    PDF »
Saturation Density of Skin Fibroblasts as a Quantitative Screen for Human Cancer Susceptibility.
H. Rubin (2009)
Cancer Epidemiol. Biomarkers Prev. 18, 2366-2372
   Abstract »    Full Text »    PDF »
Multiplex padlock targeted sequencing reveals human hypermutable CpG variations.
J. B. Li, Y. Gao, J. Aach, K. Zhang, G. V. Kryukov, B. Xie, A. Ahlford, J.-K. Yoon, A. M. Rosenbaum, A. W. Zaranek, et al. (2009)
Genome Res. 19, 1606-1615
   Abstract »    Full Text »    PDF »
Identification of rare cancer driver mutations by network reconstruction.
A. Torkamani and N. J. Schork (2009)
Genome Res. 19, 1570-1578
   Abstract »    Full Text »    PDF »
Fluorescence In Situ Hybridization to Visualize Genetic Abnormalities in Interphase Cells of Acinar Cell Carcinoma, Ductal Adenocarcinoma, and Islet Cell Carcinoma of the Pancreas.
G. W. Dewald, T. C. Smyrk, E. C. Thorland, R. R. McWilliams, D. L. Van Dyke, J. G. Keefe, K. J. Belongie, S. A. Smoley, D. L. Knutson, S. R. Fink, et al. (2009)
Mayo Clin. Proc. 84, 801-810
   Abstract »    Full Text »    PDF »
Cancer-Specific High-Throughput Annotation of Somatic Mutations: Computational Prediction of Driver Missense Mutations.
H. Carter, S. Chen, L. Isik, S. Tyekucheva, V. E. Velculescu, K. W. Kinzler, B. Vogelstein, and R. Karchin (2009)
Cancer Res. 69, 6660-6667
   Abstract »    Full Text »    PDF »
Phase III, Randomized Study of Gemcitabine and Oxaliplatin Versus Gemcitabine (fixed-dose rate infusion) Compared With Gemcitabine (30-minute infusion) in Patients With Pancreatic Carcinoma E6201: A Trial of the Eastern Cooperative Oncology Group.
E. Poplin, Y. Feng, J. Berlin, M. L. Rothenberg, H. Hochster, E. Mitchell, S. Alberts, P. O'Dwyer, D. Haller, P. Catalano, et al. (2009)
J. Clin. Oncol. 27, 3778-3785
   Abstract »    Full Text »    PDF »
Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia.
I. Radtke, C. G. Mullighan, M. Ishii, X. Su, J. Cheng, J. Ma, R. Ganti, Z. Cai, S. Goorha, S. B. Pounds, et al. (2009)
PNAS 106, 12944-12949
   Abstract »    Full Text »    PDF »
High-throughput molecular analysis in lung cancer: insights into biology and potential clinical applications.
S. Ocak, M. L. Sos, R. K. Thomas, and P. P. Massion (2009)
Eur. Respir. J. 34, 489-506
   Abstract »    Full Text »    PDF »
Paracrine Hedgehog Signaling in Cancer.
J.-W. Theunissen and F. J. de Sauvage (2009)
Cancer Res. 69, 6007-6010
   Abstract »    Full Text »    PDF »
Organotypic Culture Model of Pancreatic Cancer Demonstrates that Stromal Cells Modulate E-Cadherin, {beta}-Catenin, and Ezrin Expression in Tumor Cells.
F. E.M. Froeling, T. A. Mirza, R. M. Feakins, A. Seedhar, G. Elia, I. R. Hart, and H. M. Kocher (2009)
Am. J. Pathol. 175, 636-648
   Abstract »    Full Text »    PDF »
MAP4K3 modulates cell death via the post-transcriptional regulation of BH3-only proteins.
D. Lam, D. Dickens, E. B. Reid, S. H. Y. Loh, N. Moisoi, and L. M. Martins (2009)
PNAS 106, 11978-11983
   Abstract »    Full Text »    PDF »
A Genome-wide Short Hairpin RNA Screening of Jurkat T-cells for Human Proteins Contributing to Productive HIV-1 Replication.
M. L. Yeung, L. Houzet, V. S. R. K. Yedavalli, and K.-T. Jeang (2009)
J. Biol. Chem. 284, 19463-19473
   Abstract »    Full Text »    PDF »
Secretion of Tumor-Specific Antigen by Myeloma Cells Is Required for Cancer Immunosurveillance by CD4+ T Cells.
A. Corthay, K. U. Lundin, K. B. Lorvik, P. O. Hofgaard, and B. Bogen (2009)
Cancer Res. 69, 5901-5907
   Abstract »    Full Text »    PDF »
Sample Type Bias in the Analysis of Cancer Genomes.
D. A. Solomon, J.-S. Kim, H. W. Ressom, Z. Sibenaller, T. Ryken, W. Jean, D. Bigner, H. Yan, and T. Waldman (2009)
Cancer Res. 69, 5630-5633
   Abstract »    Full Text »    PDF »
SMAD4 Gene Mutations Are Associated with Poor Prognosis in Pancreatic Cancer.
A. Blackford, O. K. Serrano, C. L. Wolfgang, G. Parmigiani, S. Jones, X. Zhang, D. W. Parsons, J. C.-H. Lin, R. J. Leary, J. R. Eshleman, et al. (2009)
Clin. Cancer Res. 15, 4674-4679
   Abstract »    Full Text »    PDF »
Cancer Genome Sequencing--An Interim Analysis.
E. J. Fox, J. J. Salk, and L. A. Loeb (2009)
Cancer Res. 69, 4948-4950
   Abstract »    Full Text »    PDF »
Genetic Inactivation of ADAMTS15 Metalloprotease in Human Colorectal Cancer.
C. G. Viloria, A. J. Obaya, A. Moncada-Pazos, M. Llamazares, A. Astudillo, G. Capella, S. Cal, and C. Lopez-Otin (2009)
Cancer Res. 69, 4926-4934
   Abstract »    Full Text »    PDF »
Challenges in the Search for Drugs to Treat Central Nervous System Disorders.
S. J. Enna and M. Williams (2009)
J. Pharmacol. Exp. Ther. 329, 404-411
   Abstract »    Full Text »    PDF »
Genetic Mutations Associated with Cigarette Smoking in Pancreatic Cancer.
A. Blackford, G. Parmigiani, T. W. Kensler, C. Wolfgang, S. Jones, X. Zhang, D. W. Parsons, J. C.-H. Lin, R. J. Leary, J. R. Eshleman, et al. (2009)
Cancer Res. 69, 3681-3688
   Abstract »    Full Text »    PDF »
Exomic Sequencing Identifies PALB2 as a Pancreatic Cancer Susceptibility Gene.
S. Jones, R. H. Hruban, M. Kamiyama, M. Borges, X. Zhang, D. W. Parsons, J. C.-H. Lin, E. Palmisano, K. Brune, E. M. Jaffee, et al. (2009)
Science 324, 217
   Abstract »    Full Text »    PDF »
Absence of Deleterious Palladin Mutations in Patients with Familial Pancreatic Cancer.
A. P. Klein, M. Borges, M. Griffith, K. Brune, S.-M. Hong, N. Omura, R. H. Hruban, and M. Goggins (2009)
Cancer Epidemiol. Biomarkers Prev. 18, 1328-1330
   Abstract »    Full Text »    PDF »
Multiple Genes Exhibit Phenobarbital-Induced Constitutive Active/Androstane Receptor-Mediated DNA Methylation Changes during Liver Tumorigenesis and in Liver Tumors.
J. M. Phillips and J. I. Goodman (2009)
Toxicol. Sci. 108, 273-289
   Abstract »    Full Text »    PDF »
Ligand-dependent Notch Signaling Is Involved in Tumor Initiation and Tumor Maintenance in Pancreatic Cancer.
M. E. Mullendore, J.-B. Koorstra, Y.-M. Li, G. J. Offerhaus, X. Fan, C. M. Henderson, W. Matsui, C. G. Eberhart, A. Maitra, and G. Feldmann (2009)
Clin. Cancer Res. 15, 2291-2301
   Abstract »    Full Text »    PDF »
Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis.
H. Tian, C. A. Callahan, K. J. DuPree, W. C. Darbonne, C. P. Ahn, S. J. Scales, and F. J. de Sauvage (2009)
PNAS 106, 4254-4259
   Abstract »    Full Text »    PDF »
A panel of isogenic human cancer cells suggests a therapeutic approach for cancers with inactivated p53.
S. Sur, R. Pagliarini, F. Bunz, C. Rago, L. A. Diaz Jr., K. W. Kinzler, B. Vogelstein, and N. Papadopoulos (2009)
PNAS 106, 3964-3969
   Abstract »    Full Text »    PDF »
Tumor-Induced Suppression of CTL Expansion and Subjugation by gp96-Ig Vaccination.
T. H. Schreiber, V. V. Deyev, J. D. Rosenblatt, and E. R. Podack (2009)
Cancer Res. 69, 2026-2033
   Abstract »    Full Text »    PDF »
Is Anticancer Drug Development Heading in the Right Direction?.
T. W. Hambley and W. N. Hait (2009)
Cancer Res. 69, 1259-1262
   Abstract »    Full Text »    PDF »
GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation.
O. Nolan-Stevaux, J. Lau, M. L. Truitt, G. C. Chu, M. Hebrok, M. E. Fernandez-Zapico, and D. Hanahan (2009)
Genes & Dev. 23, 24-36
   Abstract »    Full Text »    PDF »
IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas.
K. Ichimura, D. M. Pearson, S. Kocialkowski, L. M. Backlund, R. Chan, D. T.W. Jones, and V. P. Collins (2009)
Neuro-oncol 11, 341-347
   Abstract »    Full Text »    PDF »
MODBASE, a database of annotated comparative protein structure models and associated resources.
U. Pieper, N. Eswar, B. M. Webb, D. Eramian, L. Kelly, D. T. Barkan, H. Carter, P. Mankoo, R. Karchin, M. A. Marti-Renom, et al. (2009)
Nucleic Acids Res. 37, D347-D354
   Abstract »    Full Text »    PDF »
Enzymes and Cancer: A Look Toward the Past as We Move Forward.
K. I. Block (2008)
Integr Cancer Ther 7, 223-225
   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 »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)