Publication Date:
2008-09-06
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848990/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2848990/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jones, Sian -- Zhang, Xiaosong -- Parsons, D Williams -- Lin, Jimmy Cheng-Ho -- Leary, Rebecca J -- Angenendt, Philipp -- Mankoo, Parminder -- Carter, Hannah -- Kamiyama, Hirohiko -- Jimeno, Antonio -- Hong, Seung-Mo -- Fu, Baojin -- Lin, Ming-Tseh -- Calhoun, Eric S -- Kamiyama, Mihoko -- Walter, Kimberly -- Nikolskaya, Tatiana -- Nikolsky, Yuri -- Hartigan, James -- Smith, Douglas R -- Hidalgo, Manuel -- Leach, Steven D -- Klein, Alison P -- Jaffee, Elizabeth M -- Goggins, Michael -- Maitra, Anirban -- Iacobuzio-Donahue, Christine -- Eshleman, James R -- Kern, Scott E -- Hruban, Ralph H -- Karchin, Rachel -- Papadopoulos, Nickolas -- Parmigiani, Giovanni -- Vogelstein, Bert -- Velculescu, Victor E -- Kinzler, Kenneth W -- CA121113/CA/NCI NIH HHS/ -- CA43460/CA/NCI NIH HHS/ -- CA57345/CA/NCI NIH HHS/ -- CA62924/CA/NCI NIH HHS/ -- P50 CA062924/CA/NCI NIH HHS/ -- P50 CA062924-130011/CA/NCI NIH HHS/ -- P50 CA062924-140011/CA/NCI NIH HHS/ -- P50 CA062924-160017/CA/NCI NIH HHS/ -- R01 CA121113/CA/NCI NIH HHS/ -- R01 CA121113-04/CA/NCI NIH HHS/ -- R37 CA043460/CA/NCI NIH HHS/ -- R37 CA043460-27/CA/NCI NIH HHS/ -- R37 CA057345/CA/NCI NIH HHS/ -- R37 CA057345-17/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2008 Sep 26;321(5897):1801-6. doi: 10.1126/science.1164368. Epub 2008 Sep 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sol Goldman Pancreatic Cancer Research Center, Ludwig Center and Howard Hughes Medical Institute at the Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18772397" target="_blank"〉PubMed〈/a〉
Keywords:
Adenocarcinoma/etiology/*genetics/*metabolism
;
Algorithms
;
Carcinoma, Pancreatic Ductal/etiology/genetics/metabolism
;
Computational Biology
;
Gene Amplification
;
Gene Expression Profiling
;
Genome, Human
;
Humans
;
Models, Molecular
;
*Mutation
;
Mutation, Missense
;
Oligonucleotide Array Sequence Analysis
;
Pancreatic Neoplasms/etiology/*genetics/*metabolism
;
Point Mutation
;
Polymorphism, Single Nucleotide
;
Sequence Deletion
;
Signal Transduction/*genetics
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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