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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Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation
Giulia Fabbri,Silvia Rasi,Davide Rossi,Vladimir Trifonov,Hossein Khiabanian,Jing Ma,Adina Grunn,Marco Fangazio,Daniela Capello,Sara Monti,Stefania Cresta,Ernesto Gargiulo,Francesco Forconi,Anna Guarini,Luca Arcaini,Marco Paulli,Luca Laurenti,Luigi Maria Larocca,Roberto Marasca,Valter Gattei,David Oscier,Francesco Bertoni,Charles G. Mullighan,Robin Foà,Laura Pasqualucci,Raul Rabadan,Riccardo Dalla-Favera,Gianluca Gaidano +27 more
TL;DR: Next generation sequencing and copy number analysis provide insights into the complexity of the CLL coding genome, and reveal an association between NOTCH1 mutational activation and poor prognosis.
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Ras history: The saga continues.
Adrienne D. Cox,Channing J. Der +1 more
TL;DR: Ras proteins are also founding members of a large superfamily of small GTPases that regulate all key cellular processes and established the versatile role of small gTP-binding proteins in biology as mentioned in this paper.
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Cancer as a metabolic disease.
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Presence of Somatic Mutations in Most Early-Stage Pancreatic Intraepithelial Neoplasia
Mitsuro Kanda,Hanno Matthaei,Jian Wu,Seung-Mo Hong,Jun Yu,Michael Borges,Ralph H. Hruban,Anirban Maitra,Kenneth W. Kinzler,Bert Vogelstein,Michael Goggins +10 more
TL;DR: It is shown that more than 99% of the earliest-stage, lowest-grade, pancreatic intraepithelial neoplasm-1 lesions contain mutations in KRAS, p16/CDKN2A, GNAS, or BRAF, which could improve the understanding of the development and progression of these premalignant lesions.
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Diverse somatic mutation patterns and pathway alterations in human cancers
TL;DR: This study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.
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