Sleeping Beauty mutagenesis reveals cooperating mutations and pathways in pancreatic adenocarcinoma.
Pancreatic cancer is one of the most deadly cancers affecting the Western world. Because the disease is highly metastatic and is difficult to diagnosis until late stages, the 5-year survival rate is around 5%. The identification of molecular cancer drivers is critical to furthering our understanding of the disease and for the 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 adenocarcinoma. 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). Seventy-five of these CCGs, including Mll3, Myo1d and Ptk2, have known mutations in human pancreatic cancer. Many additional CCGs, such as Pten and Usp9x, have known mutations in human solid tumors but not in pancreatic cancer. We identified point mutations in human pancreatic patient samples for three CCGs, Macf1, Pum2 and Slmap. 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. Twenty CCGs, including Ctnnd1, Fbxo11 and Vgll4, are significantly associated with poor patient survival. Our results highlight many new cancer drivers that may play a role in pancreatic cancer. SB mutagenesis provides a rich resource of mutations for cross-comparative analyses with ongoing sequencing efforts in human pancreatic adenocarcinoma.
|Authors||Mann, K.M.; Ward, J.M.; Yew, C.C.K.; Kovochich, A.; Dawson, D.W.; Black, M.A.; Brett, B.T.; Sheets, T.E.; Dupuy, A.J.; Chang, D.K.; Biankin, A.V.; Waddell, N.; Kassahn, K.S.; Grimmond, S.; Rust, A.G.; Adams, D.J.; Jenkins, N.A.; Copeland, N.G.|
|Published Date||2012-04-17 00:00:00|
|OpenAccess Link||https://publications.gimr.garvan.org.au/download.php?11193_11908/12 Mann PNAS_oa.pdf|