Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma

Mann, Karen M., Ward, Jerrold M., Yew, Christopher Chin Kuan, Kovochich, Anne, Dawson, David W., Black, Michael A., Brett, Benjamin T., Sheetz, Benjamin T., Dupuy, Adam J., Chang, David K., Biankin, Andrew V., Waddell, Nicola, Kassahn, Karin S., Grimmond, Sean M., Rust, Alistair G., Adams, David J., Jenkins, Nancy A., Copeland, Neal G., Australian Pancreatic Cancer Genome Initiative, Miller, David K., Wilson, Peter J., Patch, Ann-Marie, Song, Sarah, Harliwong, Ivon, Idrisoglu, Senel, Nourse, Craig, Nourbakhsh, Ehsan, Manning, Suzanne, Wani, Shivangi, Gongora, Milena, Anderson, Matthew, Holmes, Oliver, Leonard, Conrad, Taylor, Darrin, Wood, Scott, Xu, Christina, Nones, Katia, Fink, J. Lynn, Christ, Angelika, Bruxner, Tim, Cloonan, Nicole, Newell, Felicity and Pearson, John V. (2012) Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma. Proceedings of the National Academy of Sciences of the United States of America, 109 16: 5934-5941. doi:10.1073/pnas.1202490109


Author Mann, Karen M.
Ward, Jerrold M.
Yew, Christopher Chin Kuan
Kovochich, Anne
Dawson, David W.
Black, Michael A.
Brett, Benjamin T.
Sheetz, Benjamin T.
Dupuy, Adam J.
Chang, David K.
Biankin, Andrew V.
Waddell, Nicola
Kassahn, Karin S.
Grimmond, Sean M.
Rust, Alistair G.
Adams, David J.
Jenkins, Nancy A.
Copeland, Neal G.
Australian Pancreatic Cancer Genome Initiative
Miller, David K.
Wilson, Peter J.
Patch, Ann-Marie
Song, Sarah
Harliwong, Ivon
Idrisoglu, Senel
Nourse, Craig
Nourbakhsh, Ehsan
Manning, Suzanne
Wani, Shivangi
Gongora, Milena
Anderson, Matthew
Holmes, Oliver
Leonard, Conrad
Taylor, Darrin
Wood, Scott
Xu, Christina
Nones, Katia
Fink, J. Lynn
Christ, Angelika
Bruxner, Tim
Cloonan, Nicole
Newell, Felicity
Pearson, John V.
Total Author Count Override 138
Title Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma
Formatted title
Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma
Journal name Proceedings of the National Academy of Sciences of the United States of America   Check publisher's open access policy
ISSN 0027-8424
1091-6490
Publication date 2012-04-01
Sub-type Article (original research)
DOI 10.1073/pnas.1202490109
Open Access Status Not Open Access
Volume 109
Issue 16
Start page 5934
End page 5941
Total pages 8
Place of publication Washington DC, United States
Publisher National Academy of Sciences
Collection year 2013
Language eng
Formatted 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.
Keyword Tumor-cell survival
Ductal adenocarcinoma
Intestinal tumorigenesis
Colorectal cancers
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2009.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
Institute for Molecular Bioscience - Publications
 
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