Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms

Shelli M Morris; Jerry Davison; Kelly T Carter; Rachele M O'Leary; Patty Trobridge; Sue E Knoblaugh; Lois L Myeroff; Sanford D Markowitz; Benjamin T Brett; Todd E Scheetz; Adam J Dupuy; Timothy K Starr; William M Grady

doi:10.1002/ijc.30491

Back

Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms

Journal article

Open access

Peer reviewed

Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms

Shelli M Morris, Jerry Davison, Kelly T Carter, Rachele M O'Leary, Patty Trobridge, Sue E Knoblaugh, Lois L Myeroff, Sanford D Markowitz, Benjamin T Brett, Todd E Scheetz, …

International journal of cancer, Vol.140(4), pp.853-863

02/15/2017

DOI: 10.1002/ijc.30491

PMCID: PMC5316486

PMID: 27790711

Files and links (1)

url

https://doi.org/10.1002/ijc.30491View

Published (Version of record) Open Access

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.

Protein-Serine-Threonine Kinases - deficiency

Receptors, Transforming Growth Factor beta - genetics

Species Specificity

Adenoma - genetics

Colorectal Neoplasms - genetics

Genes, Neoplasm

Humans

Neoplasm Proteins - physiology

Adenoma - metabolism

Adenocarcinoma - metabolism

Adenocarcinoma - genetics

Genes, Tumor Suppressor

Colorectal Neoplasms - metabolism

Protein-Serine-Threonine Kinases - genetics

Transforming Growth Factor beta - physiology

Genetic Association Studies - methods

Mice, Transgenic

Signal Transduction - genetics

Sequence Analysis, DNA

DNA Transposable Elements

Mice, Knockout

Animals

Signal Transduction - physiology

Mice

Mutagenesis, Insertional

Receptors, Transforming Growth Factor beta - deficiency

Details

Title: Subtitle: Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms
Creators: Shelli M Morris - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Jerry Davison - Public Health Sciences Division, Genomics and Bioinformatics Shared Resource, Fred Hutchinson Cancer Research Center, Seattle, WA
Kelly T Carter - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Rachele M O'Leary - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Patty Trobridge - Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
Sue E Knoblaugh - Department of Veterinary Biosciences, The Ohio State University, Columbus, OH
Lois L Myeroff - Department of Medicine, Case Western Reserve University, Cleveland, OH
Sanford D Markowitz - Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH
Benjamin T Brett - Center for Bioinformatics and Computational Biology, University of Iowa, Iowa City, IA
Todd E Scheetz - Department of Ophthalmology and Visual Sciences, Roy J. & Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
Adam J Dupuy - Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
Timothy K Starr - Department of Genetics, Cell Biology & Development, University of Minnesota, Minneapolis, MN
William M Grady - Department of Medicine, University of Washington School of Medicine, Seattle, WA
Resource Type: Journal article
Publication Details: International journal of cancer, Vol.140(4), pp.853-863
Publisher: United States
DOI: 10.1002/ijc.30491
PMID: 27790711
PMCID: PMC5316486
ISSN: 0020-7136
eISSN: 1097-0215
Grant note: R35 CA197442 / NCI NIH HHS U01 CA152756 / NCI NIH HHS U54 CA163060 / NCI NIH HHS U54 CA143862 / NCI NIH HHS P50 CA150964 / NCI NIH HHS R00 CA151672 / NCI NIH HHS P30 CA015704 / NCI NIH HHS P30 CA077598 / NCI NIH HHS R01 CA194663 / NCI NIH HHS P30 CA086862 / NCI NIH HHS T32 CA080416 / NCI NIH HHS
Language: English
Date published: 02/15/2017
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Electrical and Computer Engineering; Anatomy and Cell Biology; Pathology; Ophthalmology and Visual Sciences
Record Identifier: 9983979979002771

Metrics

21 Record Views

20 Times Cited - Web of Science

See more details