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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Yap1 Activation Enables Bypass of Oncogenic Kras Addiction in Pancreatic Cancer
Avnish Kapoor,Wantong Yao,Haoqiang Ying,Sujun Hua,Alison Liewen,Qiuyun Wang,Yi Zhong,Chang-Jiun Wu,Anguraj Sadanandam,Anguraj Sadanandam,Baoli Hu,Qing Chang,Gerald C. Chu,Ramsey Al-Khalil,Shan Jiang,Hongai Xia,Eliot Fletcher-Sananikone,Carol Lim,Gillian I. Horwitz,Andrea Viale,Piergiorgio Pettazzoni,Nora S. Sanchez,Huamin Wang,Alexei Protopopov,Jianhua Zhang,Timothy P. Heffernan,Randy L. Johnson,Lynda Chin,Y. Alan Wang,Giulio Draetta,Ronald A. DePinho +30 more
TL;DR: It is shown that some tumors undergo spontaneous relapse and are devoid of Kras(G12D) expression and downstream canonical MAPK signaling and instead acquire amplification and overexpression of the transcriptional coactivator Yap1.
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IDH1 mutations are present in the majority of common adult gliomas but rare in primary glioblastomas
Koichi Ichimura,Danita M. Pearson,Sylvia Kocialkowski,L. Magnus Bäcklund,Raymond Chan,David T.W. Jones,V. Peter Collins +6 more
TL;DR: The data indicate that IDH1 mutation combined with either TP53 mutation or total 1p/19q loss is a frequent and early change in the majority of oligodendroglial tumors, diffuse astrocytomas, anaplastic astro CYTomas, and secondary glioblastomas but not in primary gliOBlastomas.
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A Revised Classification System and Recommendations From the Baltimore Consensus Meeting for Neoplastic Precursor Lesions in the Pancreas.
Olca Basturk,Seung-Mo Hong,Laura D. Wood,N. Volkan Adsay,Jorge Albores-Saavedra,Andrew V. Biankin,Lodewijk A.A. Brosens,Noriyoshi Fukushima,Michael Goggins,Ralph H. Hruban,Yo Kato,David S. Klimstra,Günter Klöppel,Alyssa M. Krasinskas,Daniel S. Longnecker,Hanno Matthaei,G. Johan A. Offerhaus,Michio Shimizu,Kyoichi Takaori,Benoit Terris,Shinichi Yachida,Irene Esposito,Toru Furukawa +22 more
TL;DR: International experts met to discuss recent advances and to revise the 2004 recommendations for assessing and reporting precursor lesions to invasive carcinomas of the pancreas, including pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasm, and other lesions.
Journal ArticleDOI
Whole-exome sequencing of neoplastic cysts of the pancreas reveals recurrent mutations in components of ubiquitin-dependent pathways
Jian Wu,Yuchen Jiao,Marco Dal Molin,Anirban Maitra,Roeland F. de Wilde,Laura D. Wood,James R. Eshleman,Michael Goggins,Christopher L. Wolfgang,Marcia I. Canto,Richard D. Schulick,Barish H. Edil,Michael A. Choti,Volkan Adsay,David S. Klimstra,G. Johan A. Offerhaus,Alison P. Klein,Levy Kopelovich,Hannah Carter,Rachel Karchin,Peter J. Allen,C. Max Schmidt,Yoshiki Naito,Luis A. Diaz,Kenneth W. Kinzler,Nickolas Papadopoulos,Ralph H. Hruban,Bert Vogelstein +27 more
TL;DR: The preponderance of inactivating mutations in RNF43 unequivocally establish it as a suppressor of both IPMNs and MCNs, highlighting the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors.
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KRAS: feeding pancreatic cancer proliferation
TL;DR: A number of studies have shown that oncogenic KRAS plays a central role in controlling tumor metabolism by orchestrating multiple metabolic changes including stimulation of glucose uptake, differential channeling of glucose intermediates, reprogrammed glutamine metabolism, increased autophagy, and macropinocytosis.
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