title: Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms.
abstract: Colorectal cancer (CRC) results from the accumulation of gene mutations and epigenetic alterations in colon epithelial cells, which promotes CRC formation through deregulating signaling pathways. One of the most commonly deregulated signaling pathways in CRC is the transforming growth factor β (TGF-β) pathway. Importantly, the effects of TGF-β signaling inactivation in CRC are modified by concurrent mutations in the tumor cell, and these concurrent mutations determine the ultimate biological effects of impaired TGF-β signaling in the tumor. However, many of the mutations that cooperate with the deregulated TGF-β signaling pathway in CRC remain unknown. Therefore, we sought to identify candidate driver genes that promote the formation of CRC in the setting of TGF-β signaling inactivation. We performed a forward genetic screen in mice carrying conditionally inactivated alleles of the TGF-β receptor, type II (Tgfbr2) using Sleeping Beauty (SB) transposon mediated mutagenesis. We used TAPDANCE and Gene-centric statistical methods to identify common insertion sites (CIS) and, thus, candidate tumor suppressor genes and oncogenes within the tumor genome. CIS analysis of multiple neoplasms from these mice identified many candidate Tgfbr2 cooperating genes and the Wnt/β-catenin, Hippo and MAPK pathways as the most commonly affected pathways. Importantly, the majority of candidate genes were also found to be mutated in human CRC. The SB transposon system provides an unbiased method to identify Tgfbr2 cooperating genes in mouse CRC that are functionally relevant and that may provide further insight into the pathogenesis of human CRC.
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors: Shelli M
authors: SM
authors: Morris
authors: Public Health Sciences Division, Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors: Jerry
authors: J
authors: Davison
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors: Kelly T
authors: KT
authors: Carter
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors: Rachele M
authors: RM
authors: O'Leary
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
authors: Patty
authors: P
authors: Trobridge
authors: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH.
authors: Sue E
authors: SE
authors: Knoblaugh
authors: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH.|Department of Medicine, Case Western Reserve University, Cleveland, OH.
authors: Lois L
authors: LL
authors: Myeroff
authors: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH.|Department of Medicine, Case Western Reserve University, Cleveland, OH.|Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH.
authors: Sanford D
authors: SD
authors: Markowitz
authors: Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, IA.
authors: Benjamin T
authors: BT
authors: Brett
authors: Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, IA.|Department of Ophthalmology and Visual Sciences, Roy J. & Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.
authors: Todd E
authors: TE
authors: Scheetz
authors: Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.|Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA.
authors: Adam J
authors: AJ
authors: Dupuy
authors: Department of Obstetrics, Gynecology & Women's Health, Masonic Cancer Center, University of Minnesota, Minneapolis, MN.|Department of Genetics, Cell Biology & Development, University of Minnesota, Minneapolis, MN.
authors: Timothy K
authors: TK
authors: Starr
authors: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA.|Department of Medicine, University of Washington School of Medicine, Seattle, WA.
authors: William M
authors: WM
authors: Grady
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000378:metabolism; D000236:Adenoma / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D004251:DNA Transposable Elements; D052138:Genes, Neoplasm; D016147:Genes, Tumor Suppressor; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D009363:Neoplasm Proteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics* / Q000502:physiology; D013045:Species Specificity; D016212:Transforming Growth Factor beta / Q000502:physiology*
chemical_list: D004251:DNA Transposable Elements; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Sleeping Beauty; Tgfbr2; colon; colorectal cancer; genetic screen