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Originally published in Science Express on 4 September 2008 Science 26 September 2008: Vol. 321. no. 5897, pp. 1801 - 1806
DOI: 10.1126/science.1164368
Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses
Siân Jones,1*Xiaosong Zhang,1*D. Williams Parsons,1,2*Jimmy Cheng-Ho Lin,1*Rebecca J. Leary,1*Philipp Angenendt,1*Parminder Mankoo,3Hannah Carter,3Hirohiko Kamiyama,4Antonio Jimeno,1Seung-Mo Hong,4Baojin Fu,4Ming-Tseh Lin,4Eric S. Calhoun,1Mihoko Kamiyama,4Kimberly Walter,4Tatiana Nikolskaya,5Yuri Nikolsky,6James Hartigan,7Douglas R. Smith,7Manuel Hidalgo,1Steven D. Leach,1,8Alison P. Klein,1,4Elizabeth M. Jaffee,1,4Michael Goggins,1,4Anirban Maitra,1,4Christine Iacobuzio-Donahue,1,4James R. Eshleman,1,4Scott E. Kern,1,4Ralph H. Hruban,1,4Rachel Karchin,3Nickolas Papadopoulos,1Giovanni Parmigiani,1,9Bert Vogelstein,1Victor E. Velculescu,1Kenneth W. Kinzler1
There are currently few therapeutic options for patients withpancreatic cancer, and new insights into the pathogenesis ofthis lethal disease are urgently needed. Toward this end, weperformed a comprehensive genetic analysis of 24 pancreaticcancers. 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 amplificationsin the tumor DNA by using microarrays containing probes for106 single-nucleotide polymorphisms. We found that pancreaticcancers contain an average of 63 genetic alterations, the majorityof which are point mutations. These alterations defined a coreset of 12 cellular signaling pathways and processes that wereeach genetically altered in 67 to 100% of the tumors. Analysisof these tumors' transcriptomes with next-generation sequencing-by-synthesistechnologies provided independent evidence for the importanceof these pathways and processes. Our data indicate that geneticallyaltered core pathways and regulatory processes only become evidentonce the coding regions of the genome are analyzed in depth.Dysregulation of these core pathways and processes through mutationcan explain the major features of pancreatic tumorigenesis.
1 Sol Goldman Pancreatic Cancer Research Center, Ludwig Center and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA. 2 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, Incorporated, St. Joseph, MI 49085, USA. 7 Agencourt Bioscience Corporation, Beverly, MA 01915, USA. 8 Department of Surgery, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA. 9 Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: bertvog{at}gmail.com (B.V.); velculescu{at}jhmi.edu (V.E.V.); kinzlke{at}jhmi.edu (K.W.K.)
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106 single-nucleotide polymorphisms. 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 importance 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. 
To whom correspondence should be addressed. E-mail: 
