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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Patterns, Timing, and Predictors of Recurrence Following Pancreatectomy for Pancreatic Ductal Adenocarcinoma
Vincent P. Groot,Neda Rezaee,Wenchuan Wu,John L. Cameron,Elliot K. Fishman,Ralph H. Hruban,Matthew J. Weiss,Lei Zheng,Christopher L. Wolfgang,Jin He +9 more
TL;DR: Specific recurrence locations have different predictive factors and possess distinct RFS curves, supporting the hypothesis that unique biological differences exist among tumors leading to distinct patterns of recurrence.
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Computational Modeling of Pancreatic Cancer Reveals Kinetics of Metastasis Suggesting Optimum Treatment Strategies
Hiroshi Haeno,Mithat Gonen,Meghan B. Davis,Joseph M. Herman,Christine A. Iacobuzio-Donahue,Franziska Michor +5 more
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Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma.
Rafael Winograd,Katelyn T. Byrne,Rebecca A. Evans,Pamela M. Odorizzi,Anders R.L. Meyer,David L. Bajor,Cynthia Clendenin,Ben Z. Stanger,Emma E. Furth,E. John Wherry,Robert H. Vonderheide +10 more
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Clinical implications of genomic alterations in the tumour and circulation of pancreatic cancer patients
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TL;DR: These analyses reveal somatic mutations in chromatin-regulating genes MLL, M LL2, MLL3 and ARID1A in 20% of patients that are associated with improved survival and have implications for new avenues of therapeutic intervention.
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What can exome sequencing do for you
TL;DR: An overview of the current and future use of next generation sequencing as it relates to whole exome sequencing in human disease by focusing on the technical capabilities, limitations and ethical issues associated with this technology in the field of genetics and human disease is provided.
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