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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Limited heterogeneity of known driver gene mutations among the metastases of individual patients with pancreatic cancer
Alvin Makohon-Moore,Ming Zhang,Johannes G. Reiter,Ivana Bozic,Benjamin L. Allen,Benjamin L. Allen,Deepanjan Kundu,Krishnendu Chatterjee,Fay Wong,Yuchen Jiao,Zachary A. Kohutek,Jungeui Hong,Marc A. Attiyeh,Breanna Javier,Laura D. Wood,Ralph H. Hruban,Martin A. Nowak,Nickolas Papadopoulos,Kenneth W. Kinzler,Bert Vogelstein,Bert Vogelstein,Christine A. Iacobuzio-Donahue +21 more
TL;DR: The genetic similarity among the founding cells of metastases was higher than that expected for any two cells randomly taken from a normal tissue and has critical and encouraging implications for the success of future targeted therapies in advanced-stage disease.
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Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation
Luc G. T. Morris,Andrew Kaufman,Yongxing Gong,Deepa Ramaswami,Logan A. Walsh,Sevin Turcan,Stephanie Eng,Kasthuri Kannan,Yilong Zou,Luke Peng,Victoria E. Banuchi,P. Paty,Zhaoshi Zeng,Efsevia Vakiani,David B. Solit,Bhuvanesh Singh,Ian Ganly,Linda M. Liau,Timothy C. Cloughesy,Paul S. Mischel,Ingo K. Mellinghoff,Timothy A. Chan +21 more
TL;DR: Recurrent somatic mutations of the Drosophila melanogaster tumor suppressor–related gene FAT1 in glioblastoma, colorectal cancer, and head and neck cancer strongly point to FAT1 as a tumor suppressing gene driving loss of chromosome 4q35, a prevalent region of deletion in cancer.
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The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma
Pedro A. Perez-Mancera,Alistair G. Rust,Louise van der Weyden,Glen Kristiansen,Allen Li,Aaron L. Sarver,Kevin A. T. Silverstein,Robert Grützmann,Daniela Aust,Petra Rümmele,Thomas Knösel,Thomas Knösel,Colin Herd,Derek L. Stemple,Ross Kettleborough,Jacqueline A. Brosnan,Ang Li,Richard A. Morgan,Spencer Knight,Jun Yu,Shane Stegeman,Lara S. Collier,Jelle ten Hoeve,Jelle ten Hoeve,Jeroen de Ridder,Alison P. Klein,Michael Goggins,Ralph H. Hruban,David K. Chang,David K. Chang,David K. Chang,Andrew V. Biankin,Andrew V. Biankin,Andrew V. Biankin,Sean M. Grimmond,Lodewyk F. A. Wessels,Lodewyk F. A. Wessels,Stephen A. Wood,Christine A. Iacobuzio-Donahue,Christian Pilarsky,David A. Largaespada,David J. Adams,David A. Tuveson +42 more
TL;DR: This work proposes that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA, and finds that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis.
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