title: Case-oriented pathways analysis in pancreatic adenocarcinoma using data from a sleeping beauty transposon mutagenesis screen.
abstract: BACKGROUND
  Mutation studies of pancreatic ductal adenocarcinoma (PDA) have revealed complicated heterogeneous genomic landscapes of the disease. These studies cataloged a number of genes mutated at high frequencies, but also report a very large number of genes mutated in lower percentages of tumors. Taking advantage of a well-established forward genetic screening technique, with the Sleeping Beauty (SB) transposon, several studies produced PDA and discovered a number of common insertion sites (CIS) and associated genes that are recurrently mutated at high frequencies. As with human mutation studies, a very large number of genes were found to be altered by transposon insertion at low frequencies. These low frequency CIS associated genes may be very valuable to consider for their roles in cancer, since collectively they might emerge from a core group of genetic pathways.
  
  
  RESULTS
  In this paper, we determined whether the genetic mutations in SB-accelerated PDA occur within a collated group of biological processes defined as gene sets. The approach considered both genes mutated in high and lower frequencies. We implemented a case-oriented, gene set enrichment analysis (CO-GSEA) on SB altered genes in PDA. Compared to traditional GSEA, CO-GSEA enables us to consider individual characteristics of mutation profiles of each PDA tumor. We identified genetic pathways with higher numbers of genetic mutations than expected by chance. We also present the correlations between these significant enriched genetic pathways, and their associations with CIS genes.
  
  
  CONCLUSIONS
  These data suggest that certain pathway alterations cooperate in PDA development.
authors.affiliation: Division of Biostatistics, School of Public Health, University of Minnesota, 420 Delaware St. SE, Minneapolis, Minnesota, USA. yho@umn.edu.|Masonic Cancer Center, University of Minnesota, 425 E River Pkwy, Minneapolis, Minnesota, USA. yho@umn.edu.
authors.forename: Yen-Yi
authors.initials: YY
authors.lastname: Ho
authors.affiliation: Masonic Cancer Center, University of Minnesota, 425 E River Pkwy, Minneapolis, Minnesota, USA.|Department of Obstetrics, Gynecology & Women's Health, MMC 395, 420 Delaware St SE, Minneapolis, MN 55455, Minnesota, USA.
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Starr
authors.affiliation: Minnesota Super Computing Institute, 599 Walter Library, 117 Pleasant Street SE, Minneapolis, MN 55455, Minnesota, USA.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: LaRue
authors.affiliation: Masonic Cancer Center, University of Minnesota, 425 E River Pkwy, Minneapolis, Minnesota, USA.|Department of Pediatrics, 2231 6th St. SE, Minneapolis, MN 55455, Minnesota, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
mesh_terms: D004251:DNA Transposable Elements / Q000235:genetics*; D005820:Genetic Testing; D006801:Humans; D016254:Mutagenesis, Insertional / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D010190:Pancreatic Neoplasms / Q000235:genetics*; D059748:Proteolysis; D015398:Signal Transduction / Q000235:genetics; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D004251:DNA Transposable Elements; D025801:Ubiquitin
keywords: CIS; Case-oriented gene set analysis; Common insertion sites; Forward genetic screen; Pathways correlations; Sleeping Beauty transposon