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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Digital next-generation sequencing identifies low-abundance mutations in pancreatic juice samples collected from the duodenum of patients with pancreatic cancer and intraductal papillary mucinous neoplasms
Jun Yu,Yoshihiko Sadakari,Koji Shindo,Masaya Suenaga,Aaron Brant,Jose Alejandro Almario,Michael Borges,Thomas Barkley,Shahriar Fesharakizadeh,Madeline Ford,Ralph H. Hruban,Eun Ji Shin,Anne Marie Lennon,Marcia Irene Canto,Michael Goggins +14 more
TL;DR: The detection in pancreatic juice of mutations important for the progression of low-grade Dysplasia to high-grade dysplasia and invasive pancreatic cancer may improve the management of patients undergoing pancreatic screening and surveillance.
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Perspectives in the treatment of pancreatic adenocarcinoma.
TL;DR: This review focuses on current understanding of the pathogenesis of PDAC and the latest developments in the treatment of advanced PDAC.
Journal ArticleDOI
Retrotransposon insertions in the clonal evolution of pancreatic ductal adenocarcinoma
Nemanja Rodić,Jared P. Steranka,Alvin Makohon-Moore,Alvin Makohon-Moore,Allison Moyer,Peilin Shen,Reema Sharma,Zachary A. Kohutek,Cheng Ran Huang,Daniel Ahn,Paolo Mita,Martin S. Taylor,Norman Barker,Ralph H. Hruban,Ralph H. Hruban,Christine A. Iacobuzio-Donahue,Jef D. Boeke,Kathleen H. Burns +17 more
TL;DR: The findings show that LINE-1 contributes to the genetic evolution of PDAC and suggest that somatic insertions are acquired discontinuously in gastrointestinal neoplasms.
Journal ArticleDOI
Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma
Zhi Rong Qian,Douglas A. Rubinson,Jonathan A. Nowak,Jonathan A. Nowak,Vicente Morales-Oyarvide,Richard F. Dunne,Margaret M. Kozak,Marisa W. Welch,Lauren K. Brais,Annacarolina da Silva,Tingting Li,Wanwan Li,Atsuhiro Masuda,Juhong Yang,Yan Shi,Mancang Gu,Yohei Masugi,Justin L. Bui,Caitlin L. Zellers,Chen Yuan,Ana Babic,Natalia Khalaf,Andrew J. Aguirre,Kimmie Ng,Rebecca A. Miksad,Andrea J. Bullock,Daniel T. Chang,Jennifer F. Tseng,Thomas E. Clancy,David C. Linehan,Jennifer J. Findeis-Hosey,Leona A. Doyle,Aaron R. Thorner,Matthew D. Ducar,Matthew D. Ducar,Bruce M. Wollison,Angelica Laing,William C. Hahn,Matthew Meyerson,Charles S. Fuchs,Shuji Ogino,Jason L. Hornick,Aram F. Hezel,Albert C. Koong,Brian M. Wolpin +44 more
TL;DR: Patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma and patient outcomes after cancer resection, and alterations of SMAD4 was not associated with DFS or OS, whereas TP53 status was associated only with shorter DFS.
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Fasting Blood Glucose Levels Provide Estimate of Duration and Progression of Pancreatic Cancer Before Diagnosis
TL;DR: In a case-control study of patients with PDAC from 2 databases, FBG level with time to PDAC diagnosis and tumor volume and grade is associated with time that they have had the tumor.
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