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  current news   Press   selected story    
     
  13th April 2012  
  Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma.
 
 




Authors
Karen M. Manna, Jerrold M. Warda, Christopher Chin Kuan Yewa, Anne Kovochichb, David W. Dawsonb, Michael A. Blackc, Benjamin T. Brettd, Todd E. Sheetzd,e,f, Adam J. Dupuyg, Australian Pancreatic Cancer Genome Initiativeh, David K. Changi,j,k, Andrew V. Biankini,j,k, Nicola Waddelll, Karin S. Kassahnl, Sean M. Grimmondl, Alistair G. Rustm David J. Adamsm, Nancy A. Jenkinsa and Neal G. Copelanda

a -
Division of Genetics and Genomics, Institute of Molecular and Cell Biology, Singapore 138673
b -
Department of Pathology and Laboratory Medicine and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at University of California, Los Angeles, CA 90095
c -
Department of Biochemistry, University of Otago, Dunedin, 9016, New Zealand
d -
Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, IA 52242
e -
Department of Biomedical Engineering, University of Iowa, Iowa City, IA 52242
f -
Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa,Iowa City, IA 52242
g -
Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City,IA 52242
h -
Australian Pancreatic Cancer Genome Initiative
i -
Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales 2010, Australia
j -
Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales 2200, Australia
k -
South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia
l -
Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia
m -
Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1HH, United Kingdom

This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2009.

Proc Natl Acad Sci , USA. 2012 Mar 15. [Epub ahead of print]

Abstract
Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and difficult to diagnosis until late stages, the 5-y survival rate is around 5%. The identification of molecular cancer drivers is critical for furthering our understanding of the disease and development of improved diagnostic tools and therapeutics. We have conducted a mutagenic screen using Sleeping Beauty (SB) in mice to identify new candidate cancer genes in pancreatic cancer. By combining SB with an oncogenic Kras allele, we observed highly metastatic pancreatic adenocarcinomas. Using two independent statistical methods to identify loci commonly mutated by SB in these tumors, we identified 681 loci that comprise 543 candidate cancer genes (CCGs); 75 of these CCGs, including Mll3 and Ptk2, have known mutations in human pancreatic cancer. We identified point mutations in human pancreatic patient samples for another 11 CCGs, including Acvr2a and Map2k4. Importantly, 10% of the CCGs are involved in chromatin remodeling, including Arid4b, Kdm6a, and Nsd3, and all SB tumors have at least one mutated gene involved in this process; 20 CCGs, including Ctnnd1, Fbxo11, and Vgll4, are also significantly associated with poor patient survival. SB mutagenesis provides a rich resource of mutations in potential cancer drivers for cross-comparative analyses with ongoing sequencing efforts in human pancreatic adenocarcinoma.


Figure Legend: Circos map of pancreatic cancer candidate cancer genes identified by GKC Method. Transposon insertions in the plus (orange lines) and minus (purple lines) strands demonstrate genome-wide coverage of mutagenesis.  GKC CCGs are illustrated on the outer perimeter of the plot with their exact location denoted by a black line.  Genes listed in red are mutated in human pancreatic cancer.  The blue lines in the center connect bolded GKC CCGs that significantly co-occur in tumors (Fisher’s Exact test P < 0.0003).

Link to citation of the paper:

http://www.sciencedaily.com/releases/2012/03/120312152643.htm