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Science 321 (5897): 1801-1806

Copyright © 2008 by the American Association for the Advancement of Science

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,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,1,8 Alison P. Klein,1,4 Elizabeth M. Jaffee,1,4 Michael Goggins,1,4 Anirban Maitra,1,4 Christine Iacobuzio-Donahue,1,4 James R. Eshleman,1,4 Scott E. Kern,1,4 Ralph H. Hruban,1,4 Rachel Karchin,3 Nickolas Papadopoulos,1 Giovanni Parmigiani,1,9 Bert Vogelstein,1{dagger} Victor E. Velculescu,1{dagger} Kenneth W. Kinzler1{dagger}

Abstract: There are currently few therapeutic options for patients with pancreatic cancer, and new insights into the pathogenesis of this lethal disease are urgently needed. Toward 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. 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.

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.

{dagger} 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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