Dataset Information

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.

SUBMITTER: Jones S

PROVIDER: S-EPMC2848990 | biostudies-literature | 2008 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.

Jones Siân S 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

Science (New York, N.Y.) 20080904 5897

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 approxim ...[more]

PMID: 18772397

Similar Datasets

Project description:Tumor recurrence occurs in more than 70% of ovarian cancer patients, and the majority eventually becomes refractory to treatments. Ovarian Cancer Stem Cells (OCSCs) are believed to be responsible for the tumor relapse and drug resistance. Therefore, eliminating ovarian CSCs is important to improve the prognosis of ovarian cancer patients. However, there is a lack of effective drugs to eliminate OCSCs because the core signaling pathways regulating OCSCs remain unclear. Also it is often hard for biologists to identify a few testable targets and infer driver signaling pathways regulating CSCs from a large number of differentially expression genes in an unbiased manner. In this study, we propose a straightforward and integrative analysis to identify potential core signaling pathways of OCSCs by integrating transcriptome data of OCSCs isolated based on two distinctive markers, ALDH and side population, with regulatory network (Transcription Factor (TF) and Target Interactome) and signaling pathways. We first identify the common activated TFs in two OCSC populations integrating the gene expression and TF-target Interactome; and then uncover up-stream signaling cascades regulating the activated TFs. In specific, 22 activated TFs are identified. Through literature search validation, 15 of them have been reported in association with cancer stem cells. Additionally, 10 TFs are found in the KEGG signaling pathways, and their up-stream signaling cascades are extracted, which also provide potential treatment targets. Moreover, 40 FDA approved drugs are identified to target on the up-stream signaling cascades, and 15 of them have been reported in literatures in cancer stem cell treatment. In conclusion, the proposed approach can uncover the activated up-stream signaling, activated TFs and up-regulated target genes that constitute the potential core signaling pathways of ovarian CSC. Also drugs and drug combinations targeting on the core signaling pathways might be able to eliminate OCSCs. The proposed approach can also be applied for identifying potential activated signaling pathways of other types of cancers.

Project description:Defining cell type-specific transcriptomes in mammals can be challenging, especially for unannotated regions of the genome. We have developed an analytical pipeline called groHMM for annotating primary transcripts using global nuclear run-on sequencing (GRO-seq) data. Herein, we use this pipeline to characterize the transcriptome of an immortalized adult human ventricular cardiomyocyte cell line (AC16) in response to signaling by tumor necrosis factor alpha (TNF?), which is controlled in part by NF-?B, a key transcriptional regulator of inflammation. A unique aspect of this work is the use of the RNA polymerase II (Pol II) inhibitor ?-amanitin, which we used to define a set of RNA polymerase I and III (Pol I and Pol III) transcripts.Using groHMM, we identified ~30,000 coding and non-coding transcribed regions in AC16 cells, which includes a set of unique Pol I and Pol III primary transcripts. Many of these transcripts have not been annotated previously, including enhancer RNAs originating from NF-?B binding sites. In addition, we observed that AC16 cells rapidly and dynamically reorganize their transcriptomes in response to TNF? stimulation in an NF-?B-dependent manner, switching from a basal state to a proinflammatory state affecting a spectrum of cardiac-associated protein-coding and non-coding genes. Moreover, we observed distinct Pol II dynamics for up- and downregulated genes, with a rapid release of Pol II into productive elongation for TNF?-stimulated genes. As expected, the TNF?-induced changes in the AC16 transcriptome resulted in corresponding changes in cognate mRNA and protein levels in a similar manner, but with delayed kinetics.Our studies illustrate how computational genomics can be used to characterize the signal-regulated transcriptome in biologically relevant cell types, providing new information about how the human genome is organized, transcribed and regulated. In addition, they show how ?-amanitin can be used to reveal the Pol I and Pol III transcriptome. Furthermore, they shed new light on the regulation of the cardiomyocyte transcriptome in response to a proinflammatory signal and help to clarify the link between inflammation and cardiomyocyte function at the transcriptional level.

Dataset Information

Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.

Publications

Core signaling pathways in human pancreatic cancers revealed by global genomic analyses.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets