{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Morris SM"],"funding":["Burroughs Wellcome Fund","National Cancer Institute","NCI NIH HHS","Fred Hutchinson/University of Washington Cancer Consortium Shared Resource Access Award","SP3 award Masonic Cancer Center","NIGMS NIH HHS"],"pagination":["853-863"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC5316486"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["140(4)"],"pubmed_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."],"journal":["International journal of cancer"],"pubmed_title":["Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms."],"pmcid":["PMC5316486"],"funding_grant_id":["T32CA080416","T32 GM008629","R01CA194663","P30 CA015704","P30 CA077598","P30CA15704","T32 CA080416","P50 CA150964","U54 CA143862","R00 CA151672","U01CA152756","U01 CA152756","P30CA77598","R01 CA194663","5P50CA150964","U54CA143862","P30 CA086862","5R00CA151672-04","U54 CA163060","R35 CA197442"],"pubmed_authors":["Starr TK","Markowitz SD","Myeroff LL","Trobridge P","Carter KT","Morris SM","O'Leary RM","Grady WM","Dupuy AJ","Davison J","Brett BT","Scheetz TE","Knoblaugh SE"],"additional_accession":[]},"is_claimable":false,"name":"Transposon mutagenesis identifies candidate genes that cooperate with loss of transforming growth factor-beta signaling in mouse intestinal neoplasms.","description":"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.","dates":{"release":"2017-01-01T00:00:00Z","publication":"2017 Feb","modification":"2024-11-06T22:45:31.968Z","creation":"2019-03-26T23:01:50Z"},"accession":"S-EPMC5316486","cross_references":{"pubmed":["27790711"],"doi":["10.1002/ijc.30491"]}}