Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.
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.
Jones
Siân
S
Sol Goldman Pancreatic Cancer Research Center, Ludwig Center and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Zhang
Xiaosong
X
Parsons
D Williams
DW
Lin
Jimmy Cheng-Ho
JC
Leary
Rebecca J
RJ
Angenendt
Philipp
P
Mankoo
Parminder
P
Carter
Hannah
H
Kamiyama
Hirohiko
H
Jimeno
Antonio
A
Hong
Seung-Mo
SM
Fu
Baojin
B
Lin
Ming-Tseh
MT
Calhoun
Eric S
ES
Kamiyama
Mihoko
M
Walter
Kimberly
K
Nikolskaya
Tatiana
T
Nikolsky
Yuri
Y
Hartigan
James
J
Smith
Douglas R
DR
Hidalgo
Manuel
M
Leach
Steven D
SD
Klein
Alison P
AP
Jaffee
Elizabeth M
EM
Goggins
Michael
M
Maitra
Anirban
A
Iacobuzio-Donahue
Christine
C
Eshleman
James R
JR
Kern
Scott E
SE
Hruban
Ralph H
RH
Karchin
Rachel
R
Papadopoulos
Nickolas
N
Parmigiani
Giovanni
G
Vogelstein
Bert
B
Velculescu
Victor E
VE
Kinzler
Kenneth W
KW
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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