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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T cell receptor repertoire features associated with survival in immunotherapy-treated pancreatic ductal adenocarcinoma
Alexander Hopkins,Mark Yarchoan,Jennifer N. Durham,Erik Yusko,Julie A. Rytlewski,Harlan Robins,Daniel A. Laheru,Dung T. Le,Eric R. Lutz,Elizabeth M. Jaffee +9 more
TL;DR: It is shown that these therapies have measurably different effects on the peripheral repertoire, consistent with their mechanisms of action, and the potential for TCR repertoire profiling to serve as a biomarker of clinical response in pancreatic cancer patients receiving immunotherapy is demonstrated.
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Function and cancer genomics of FAT family genes (review).
TL;DR: Cancer genomics of the FAT signaling cascades could be applied for diagnostics, prognostics and therapeutics in the era of personalized medicine.
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Genetic Alterations Associated With Progression From Pancreatic Intraepithelial Neoplasia to Invasive Pancreatic Tumor
Stephen J. Murphy,Steven N. Hart,Joema Felipe Lima,Benjamin R. Kipp,Mitchell Klebig,Jennifer L. Winters,Csilla Szabo,Lizhi Zhang,Bruce W. Eckloff,Gloria M. Petersen,Steven E. Scherer,Richard A. Gibbs,Robert R. McWilliams,George Vasmatzis,Fergus J. Couch +14 more
TL;DR: Early stage PanIN2 lesions appear to contain many of the somatic gene alterations required for PDAC development, and genes involved in gap junctions, the actin cytoskeleton, the mitogen-activated protein kinase signaling pathway, axon guidance, and cell-cycle regulation are among the earliest targets of mutagenesis.
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Clinical utility of circulating tumor DNA for molecular assessment in pancreatic cancer
Erina Takai,Yasushi Totoki,Hiromi Nakamura,Chigusa Morizane,Satoshi Nara,Natsuko Hama,Masami Suzuki,Eisaku Furukawa,Mamoru Kato,Hideyuki Hayashi,Takashi Kohno,Hideki Ueno,Kazuaki Shimada,Takuji Okusaka,Hitoshi Nakagama,Tatsuhiro Shibata,Shinichi Yachida +16 more
TL;DR: Assessment of mutations and copy number alterations in plasma cfDNA may provide a prognostic and diagnostic tool to assist decisions regarding optimal therapeutic strategies for PDAC patients.
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Genome-wide analysis of promoter methylation associated with gene expression profile in pancreatic adenocarcinoma
Audrey Vincent,Noriyuki Omura,Seung-Mo Hong,Andrew E. Jaffe,James R. Eshleman,Michael Goggins +5 more
TL;DR: This analysis identified 1,658 known loci that were commonly differentially methylated in pancreatic cancer compared with normal pancreas including a more comprehensive list of hypermethylated and silenced genes that have not been previously described as targets for aberrant methylation in cancer.
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