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Type: Journal article
Title: Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma
Author: Mann, K.
Ward, J.
Yew, C.
Kovochich, A.
Dawson, D.
Black, M.
Brett, B.
Sheetz, T.
Dupuy, A.
Australian Pancreatic Cancer Genome Initiative
Chang, D.
Biankin, A.
Waddell, N.
Kassahn, K.
Grimmond, S.
Rust, A.
Adams, D.
Jenkins, N.
Copeland, N.
Citation: Proceedings of the National Academy of Sciences of USA, 2012; 109(16):5934-5941
Publisher: National Academy of Sciences
Issue Date: 2012
ISSN: 0027-8424
Statement of
Karen M. Mann, Jerrold M. Ward, Christopher Chin Kuan Yew, Anne Kovochich, David W. Dawson, Michael A. Black, Benjamin T. Brett, Todd E. Sheetz, Adam J. Dupuy, Australian Pancreatic Cancer Genome Initiative, David K. Chang, Andrew V. Biankin, Nicola Waddell, Karin S. Kassahn, Sean M. Grimmond, Alistair G. Rust, David J. Adams, Nancy A. Jenkins, and Neal G. Copeland
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.
Description: This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2009.
Rights: Copyright the authors
DOI: 10.1073/pnas.1202490109
Appears in Collections:Aurora harvest 7
Molecular and Biomedical Science publications

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