title: Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.
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.
authors.affiliation: Sol Goldman Pancreatic Cancer Research Center, Ludwig Center and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
authors.forename: Siân
authors.initials: S
authors.lastname: Jones
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Zhang
authors.forename: D Williams
authors.initials: DW
authors.lastname: Parsons
authors.forename: Jimmy Cheng-Ho
authors.initials: JC
authors.lastname: Lin
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Leary
authors.forename: Philipp
authors.initials: P
authors.lastname: Angenendt
authors.forename: Parminder
authors.initials: P
authors.lastname: Mankoo
authors.forename: Hannah
authors.initials: H
authors.lastname: Carter
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Kamiyama
authors.forename: Antonio
authors.initials: A
authors.lastname: Jimeno
authors.forename: Seung-Mo
authors.initials: SM
authors.lastname: Hong
authors.forename: Baojin
authors.initials: B
authors.lastname: Fu
authors.forename: Ming-Tseh
authors.initials: MT
authors.lastname: Lin
authors.forename: Eric S
authors.initials: ES
authors.lastname: Calhoun
authors.forename: Mihoko
authors.initials: M
authors.lastname: Kamiyama
authors.forename: Kimberly
authors.initials: K
authors.lastname: Walter
authors.forename: Tatiana
authors.initials: T
authors.lastname: Nikolskaya
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nikolsky
authors.forename: James
authors.initials: J
authors.lastname: Hartigan
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Smith
authors.forename: Manuel
authors.initials: M
authors.lastname: Hidalgo
authors.forename: Steven D
authors.initials: SD
authors.lastname: Leach
authors.forename: Alison P
authors.initials: AP
authors.lastname: Klein
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
authors.forename: Michael
authors.initials: M
authors.lastname: Goggins
authors.forename: Anirban
authors.initials: A
authors.lastname: Maitra
authors.forename: Christine
authors.initials: C
authors.lastname: Iacobuzio-Donahue
authors.forename: James R
authors.initials: JR
authors.lastname: Eshleman
authors.forename: Scott E
authors.initials: SE
authors.lastname: Kern
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.forename: Rachel
authors.initials: R
authors.lastname: Karchin
authors.forename: Nickolas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
mesh_terms: D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D000465:Algorithms; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D019295:Computational Biology; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015894:Genome, Human; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D020125:Mutation, Missense; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D017384:Sequence Deletion; D015398:Signal Transduction / Q000235:genetics*
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