Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma.

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.

authors

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,Copela

doi

10.1073/pnas.1202490109

subject

Has Abstract

pub_date

2012-04-17 00:00:00

pages

5934-41

issue

16

eissn

0027-8424

issn

1091-6490

pii

1202490109

journal_volume

109

pub_type

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