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Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor‐beta signaling in mouse intestinal neoplasms
Author(s) -
Morris Shelli M.,
Davison Jerry,
Carter Kelly T.,
O'Leary Rachele M.,
Trobridge Patty,
Knoblaugh Sue E.,
Myeroff Lois L.,
Markowitz Sanford D.,
Brett Benjamin T.,
Scheetz Todd E.,
Dupuy Adam J.,
Starr Timothy K.,
Grady William M.
Publication year - 2016
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.30491
Subject(s) - biology , wnt signaling pathway , candidate gene , signal transduction , genetics , cancer research , genetic screen , gene , transforming growth factor beta , transposon mutagenesis , acvrl1 , transforming growth factor , microbiology and biotechnology , transposable element , endoglin , mutant , stem cell , cd34
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.