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.
journal_name
Proc Natl Acad Sci U S Aauthors
Mann KM,Ward JM,Yew CC,Kovochich A,Dawson DW,Black MA,Brett BT,Sheetz TE,Dupuy AJ,Australian Pancreatic Cancer Genome Initiative.,Chang DK,Biankin AV,Waddell N,Kassahn KS,Grimmond SM,Rust AG,Adams DJ,Jenkins NA,Copeladoi
10.1073/pnas.1202490109subject
Has Abstractpub_date
2012-04-17 00:00:00pages
5934-41issue
16eissn
0027-8424issn
1091-6490pii
1202490109journal_volume
109pub_type
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