Core Signaling Pathways in Human Pancreatic Cancers Revealed by Global Genomic Analyses
Siân Jones,Xiaosong Zhang,D. Williams Parsons,D. Williams Parsons,Jimmy Lin,Rebecca J. Leary,Philipp Angenendt,Parminder Mankoo,Hannah Carter,Hirohiko Kamiyama,Antonio Jimeno,Seung-Mo Hong,Baojin Fu,Ming Tseh Lin,Eric S. Calhoun,Mihoko Kamiyama,Kimberly Walter,Tatiana Nikolskaya,Yuri Nikolsky,James Hartigan,Douglas Smith,Manuel Hidalgo,Steven D. Leach,Alison P. Klein,Elizabeth M. Jaffee,Michael Goggins,Anirban Maitra,Anirban Maitra,Christine A. Iacobuzio-Donahue,James R. Eshleman,Scott E. Kern,Ralph H. Hruban,Rachel Karchin,Nickolas Papadopoulos,Giovanni Parmigiani,Bert Vogelstein,Victor E. Velculescu,Kenneth W. Kinzler +37 more
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TLDR
It is found that pancreatic cancers contain an average of 63 genetic alterations, the majority of which are point mutations, which defined a core set of 12 cellular signaling pathways and processes that were each genetically altered in 67 to 100% of the tumors.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.read more
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Inactivation of TIF1γ Cooperates with KrasG12D to Induce Cystic Tumors of the Pancreas
David F. Vincent,Kai-Ping Yan,Isabelle Treilleux,Vanessa Arfi,Bastien Kaniewsky,Julien C. Marie,Florian Lepinasse,Sylvie Martel,Sophie Goddard-Léon,Juan L. Iovanna,Pierre Dubus,Stéphane Garcia,Alain Puisieux,Ruth Rimokh,Nabeel Bardeesy,Jean-Yves Scoazec,Régine Losson,Laurent Bartholin +17 more
TL;DR: It is suggested that Tif1γ is critical for tumor suppression in the pancreas, brings new insight into the genetics of pancreatic cancer, and constitutes a promising model to decipher the respective roles of SMAD4 and TIF1γ in the multifaceted functions of TGFβ in carcinogenesis and development.
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Therapeutic options for the management of pancreatic cancer
TL;DR: The most effective therapies that have been used for the treatment of pancreatic cancer are reviewed and the future potential of therapeutic options are discussed.
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The role of wild type RAS isoforms in cancer
TL;DR: The preponderance of evidence indicates that wild type RAS proteins play a tumour promoting role when the mutant RAS is of a different isoform, which is particularly robust in KRAS mutant cancers, which often display suppression or loss of wild type KRAS, but is not as strong for NRAS.
Journal ArticleDOI
Randomized Phase 2 Trial of the Oncolytic Virus Pelareorep (Reolysin) in Upfront Treatment of Metastatic Pancreatic Adenocarcinoma
Anne M. Noonan,Matthew R. Farren,Susan Geyer,Ying Huang,Sanaa Tahiri,Daniel H. Ahn,Sameh Mikhail,Kristen K. Ciombor,Shubham Pant,Santiago Aparo,Jennifer Sexton,John L. Marshall,Thomas A. Mace,Christina Wu,Bassel F. El-Rayes,Cynthia Timmers,James A. Zwiebel,Gregory B. Lesinski,Miguel A. Villalona-Calero,Tanios Bekaii-Saab +19 more
TL;DR: Overall, pelareorep was safe but does not improve PFS when administered with carboplatin/paclitaxel, regardless of KRAS mutational status.
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PON-P: Integrated predictor for pathogenicity of missense variants†‡
TL;DR: The Pathogenic‐or‐Not‐Pipeline (PON‐P) integrates five predictors to predict the probability that nonsynonymous variations affect protein function and may consequently be disease related.
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