title: 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.affiliation: Division of Genetics and Genomics, Institute of Molecular and Cell Biology,  Singapore 138673.
authors.forename: Karen M
authors.initials: KM
authors.lastname: Mann
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.forename: Christopher Chin Kuan
authors.initials: CC
authors.lastname: Yew
authors.forename: Anne
authors.initials: A
authors.lastname: Kovochich
authors.forename: David W
authors.initials: DW
authors.lastname: Dawson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Black
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Brett
authors.forename: Todd E
authors.initials: TE
authors.lastname: Sheetz
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Dupuy
authors.forename: David K
authors.initials: DK
authors.lastname: Chang
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Biankin
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.forename: Karin S
authors.initials: KS
authors.lastname: Kassahn
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D051177:Catenins / Q000235:genetics / Q000378:metabolism; D004251:DNA Transposable Elements / Q000235:genetics*; D004195:Disease Models, Animal; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D011905:Genes, ras / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009154:Mutation; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics*; D016019:Survival Analysis; D000095002:Delta Catenin
chemical_list: D051177:Catenins; D004251:DNA Transposable Elements; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D000095002:Delta Catenin