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

Siân Jones(Johns Hopkins University), Xiaosong Zhang(Johns Hopkins University), D. Williams Parsons(Johns Hopkins University), Jimmy Lin(Johns Hopkins University), Rebecca Leary(Johns Hopkins University), Philipp Angenendt(Johns Hopkins University), Parminder K. Mankoo(Johns Hopkins University), Hannah Carter(Johns Hopkins University), Hirohiko Kamiyama(Johns Hopkins University), Antonio Jimeno(Johns Hopkins University), Seung‐Mo Hong(Johns Hopkins University), Baojin Fu(Johns Hopkins University), Ming‐Tseh Lin(Johns Hopkins University), Eric S. Calhoun(Johns Hopkins University), Mihoko Kamiyama(Johns Hopkins University), Kimberly Walter(Johns Hopkins University), Tatiana Nikolskaya(Russian Academy of Sciences), Yuri Nikolsky(Johns Hopkins University), James Hartigan(Johns Hopkins University), Douglas R. Smith(Johns Hopkins University), Manuel Hidalgo(Johns Hopkins University), Steven D. Leach(Johns Hopkins University), Alison P. Klein(Johns Hopkins University), Elizabeth M. Jaffee(Johns Hopkins University), Michael Goggins(Johns Hopkins University), Anirban Maitra(Johns Hopkins University), Christine A. Iacobuzio–Donahue(Johns Hopkins University), James R. Eshleman(Johns Hopkins University), Scott E. Kern(Johns Hopkins University), Ralph H. Hruban(Johns Hopkins University), Rachel Karchin(Johns Hopkins University), Nickolas Papadopoulos(Johns Hopkins University), Giovanni Parmigiani(Johns Hopkins University), Bert Vogelstein(Johns Hopkins University), Victor E. Velculescu(Johns Hopkins University), Kenneth W. Kinzler(Johns Hopkins University)
Science
September 4, 2008
10.1126/science.1164368
Cited by 4,033Open Access
Full Text

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 approximately 10(6) 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.

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