@article{RN6110,
   author = {Lu, H. and Villafane, N. and Dogruluk, T. and Grzeskowiak, C. L. and Kong, K. and Tsang, Y. H. and Zagorodna, O. and Pantazi, A. and Yang, L. and Neill, N. J. and Kim, Y. W. and Creighton, C. J. and Verhaak, R. G. and Mills, G. B. and Park, P. J. and Kucherlapati, R. and Scott, K. L.},
   title = {Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer},
   journal = {Cancer Res},
   volume = {77},
   number = {13},
   pages = {3502-3512},
   note = {1538-7445
Lu, Hengyu
Villafane, Nicole
Dogruluk, Turgut
Grzeskowiak, Caitlin L
Kong, Kathleen
Tsang, Yiu Huen
Zagorodna, Oksana
Pantazi, Angeliki
Yang, Lixing
Neill, Nicholas J
Kim, Young Won
Creighton, Chad J
Verhaak, Roel G
Mills, Gordon B
Park, Peter J
Kucherlapati, Raju
Scott, Kenneth L
P30 CA016672/CA/NCI NIH HHS/United States
U01 CA168394/CA/NCI NIH HHS/United States
U01 CA217842/CA/NCI NIH HHS/United States
P30 CA125123/CA/NCI NIH HHS/United States
R21 CA198320/CA/NCI NIH HHS/United States
U24 CA210949/CA/NCI NIH HHS/United States
T32 GM008307/GM/NIGMS NIH HHS/United States
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
United States
2017/05/18
Cancer Res. 2017 Jul 1;77(13):3502-3512. doi: 10.1158/0008-5472.CAN-16-2745. Epub 2017 May 16.},
   abstract = {Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in The Cancer Genome Atlas datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residing within this inhibitory region may provide a means for BRAF activation in cancer, therefore we leveraged the modular design of our fusion gene construction methodology to screen N-terminal domain mutations discovered in tumors that are wild-type at the BRAF mutation hotspot, V600. We identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors. When applied broadly, these tools will facilitate rapid fusion gene construction for subsequent functional characterization and translation into personalized treatment strategies. Cancer Res; 77(13); 3502-12. ©2017 AACR.},
   keywords = {Animals
Cell Line, Tumor
Cell Transformation, Neoplastic/genetics
Female
Fusion Proteins, bcr-abl/genetics
Humans
MAP Kinase Signaling System/genetics
Mice
Mice, Nude
Mutagenesis, Site-Directed/methods
Neoplasms/*genetics
*Oncogene Fusion
Oncogene Proteins, Fusion/*genetics
Proto-Oncogene Proteins B-raf/genetics},
   ISSN = {0008-5472 (Print)
0008-5472},
   DOI = {10.1158/0008-5472.Can-16-2745},
   year = {2017},
   type = {Journal Article}
}

{"_id":"aDqsc5DYZ3sXP8q8r","bibbaseid":"lu-villafane-dogruluk-grzeskowiak-kong-tsang-zagorodna-pantazi-etal-engineeringandfunctionalcharacterizationoffusiongenesidentifiesnoveloncogenicdriversofcancer-2017","author_short":["Lu, H.","Villafane, N.","Dogruluk, T.","Grzeskowiak, C. L.","Kong, K.","Tsang, Y. H.","Zagorodna, O.","Pantazi, A.","Yang, L.","Neill, N. J.","Kim, Y. W.","Creighton, C. J.","Verhaak, R. G.","Mills, G. B.","Park, P. J.","Kucherlapati, R.","Scott, K. L."],"bibdata":{"bibtype":"article","type":"Journal Article","author":[{"propositions":[],"lastnames":["Lu"],"firstnames":["H."],"suffixes":[]},{"propositions":[],"lastnames":["Villafane"],"firstnames":["N."],"suffixes":[]},{"propositions":[],"lastnames":["Dogruluk"],"firstnames":["T."],"suffixes":[]},{"propositions":[],"lastnames":["Grzeskowiak"],"firstnames":["C.","L."],"suffixes":[]},{"propositions":[],"lastnames":["Kong"],"firstnames":["K."],"suffixes":[]},{"propositions":[],"lastnames":["Tsang"],"firstnames":["Y.","H."],"suffixes":[]},{"propositions":[],"lastnames":["Zagorodna"],"firstnames":["O."],"suffixes":[]},{"propositions":[],"lastnames":["Pantazi"],"firstnames":["A."],"suffixes":[]},{"propositions":[],"lastnames":["Yang"],"firstnames":["L."],"suffixes":[]},{"propositions":[],"lastnames":["Neill"],"firstnames":["N.","J."],"suffixes":[]},{"propositions":[],"lastnames":["Kim"],"firstnames":["Y.","W."],"suffixes":[]},{"propositions":[],"lastnames":["Creighton"],"firstnames":["C.","J."],"suffixes":[]},{"propositions":[],"lastnames":["Verhaak"],"firstnames":["R.","G."],"suffixes":[]},{"propositions":[],"lastnames":["Mills"],"firstnames":["G.","B."],"suffixes":[]},{"propositions":[],"lastnames":["Park"],"firstnames":["P.","J."],"suffixes":[]},{"propositions":[],"lastnames":["Kucherlapati"],"firstnames":["R."],"suffixes":[]},{"propositions":[],"lastnames":["Scott"],"firstnames":["K.","L."],"suffixes":[]}],"title":"Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer","journal":"Cancer Res","volume":"77","number":"13","pages":"3502-3512","note":"1538-7445 Lu, Hengyu Villafane, Nicole Dogruluk, Turgut Grzeskowiak, Caitlin L Kong, Kathleen Tsang, Yiu Huen Zagorodna, Oksana Pantazi, Angeliki Yang, Lixing Neill, Nicholas J Kim, Young Won Creighton, Chad J Verhaak, Roel G Mills, Gordon B Park, Peter J Kucherlapati, Raju Scott, Kenneth L P30 CA016672/CA/NCI NIH HHS/United States U01 CA168394/CA/NCI NIH HHS/United States U01 CA217842/CA/NCI NIH HHS/United States P30 CA125123/CA/NCI NIH HHS/United States R21 CA198320/CA/NCI NIH HHS/United States U24 CA210949/CA/NCI NIH HHS/United States T32 GM008307/GM/NIGMS NIH HHS/United States Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States 2017/05/18 Cancer Res. 2017 Jul 1;77(13):3502-3512. doi: 10.1158/0008-5472.CAN-16-2745. Epub 2017 May 16.","abstract":"Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in The Cancer Genome Atlas datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residing within this inhibitory region may provide a means for BRAF activation in cancer, therefore we leveraged the modular design of our fusion gene construction methodology to screen N-terminal domain mutations discovered in tumors that are wild-type at the BRAF mutation hotspot, V600. We identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors. When applied broadly, these tools will facilitate rapid fusion gene construction for subsequent functional characterization and translation into personalized treatment strategies. Cancer Res; 77(13); 3502-12. ©2017 AACR.","keywords":"Animals Cell Line, Tumor Cell Transformation, Neoplastic/genetics Female Fusion Proteins, bcr-abl/genetics Humans MAP Kinase Signaling System/genetics Mice Mice, Nude Mutagenesis, Site-Directed/methods Neoplasms/*genetics *Oncogene Fusion Oncogene Proteins, Fusion/*genetics Proto-Oncogene Proteins B-raf/genetics","issn":"0008-5472 (Print) 0008-5472","doi":"10.1158/0008-5472.Can-16-2745","year":"2017","bibtex":"@article{RN6110,\n author = {Lu, H. and Villafane, N. and Dogruluk, T. and Grzeskowiak, C. L. and Kong, K. and Tsang, Y. H. and Zagorodna, O. and Pantazi, A. and Yang, L. and Neill, N. J. and Kim, Y. W. and Creighton, C. J. and Verhaak, R. G. and Mills, G. B. and Park, P. J. and Kucherlapati, R. and Scott, K. L.},\n title = {Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer},\n journal = {Cancer Res},\n volume = {77},\n number = {13},\n pages = {3502-3512},\n note = {1538-7445\nLu, Hengyu\nVillafane, Nicole\nDogruluk, Turgut\nGrzeskowiak, Caitlin L\nKong, Kathleen\nTsang, Yiu Huen\nZagorodna, Oksana\nPantazi, Angeliki\nYang, Lixing\nNeill, Nicholas J\nKim, Young Won\nCreighton, Chad J\nVerhaak, Roel G\nMills, Gordon B\nPark, Peter J\nKucherlapati, Raju\nScott, Kenneth L\nP30 CA016672/CA/NCI NIH HHS/United States\nU01 CA168394/CA/NCI NIH HHS/United States\nU01 CA217842/CA/NCI NIH HHS/United States\nP30 CA125123/CA/NCI NIH HHS/United States\nR21 CA198320/CA/NCI NIH HHS/United States\nU24 CA210949/CA/NCI NIH HHS/United States\nT32 GM008307/GM/NIGMS NIH HHS/United States\nJournal Article\nResearch Support, N.I.H., Extramural\nResearch Support, Non-U.S. Gov't\nUnited States\n2017/05/18\nCancer Res. 2017 Jul 1;77(13):3502-3512. doi: 10.1158/0008-5472.CAN-16-2745. Epub 2017 May 16.},\n abstract = {Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in The Cancer Genome Atlas datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residing within this inhibitory region may provide a means for BRAF activation in cancer, therefore we leveraged the modular design of our fusion gene construction methodology to screen N-terminal domain mutations discovered in tumors that are wild-type at the BRAF mutation hotspot, V600. We identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors. When applied broadly, these tools will facilitate rapid fusion gene construction for subsequent functional characterization and translation into personalized treatment strategies. Cancer Res; 77(13); 3502-12. ©2017 AACR.},\n keywords = {Animals\nCell Line, Tumor\nCell Transformation, Neoplastic/genetics\nFemale\nFusion Proteins, bcr-abl/genetics\nHumans\nMAP Kinase Signaling System/genetics\nMice\nMice, Nude\nMutagenesis, Site-Directed/methods\nNeoplasms/*genetics\n*Oncogene Fusion\nOncogene Proteins, Fusion/*genetics\nProto-Oncogene Proteins B-raf/genetics},\n ISSN = {0008-5472 (Print)\n0008-5472},\n DOI = {10.1158/0008-5472.Can-16-2745},\n year = {2017},\n type = {Journal Article}\n}\n\n","author_short":["Lu, H.","Villafane, N.","Dogruluk, T.","Grzeskowiak, C. L.","Kong, K.","Tsang, Y. H.","Zagorodna, O.","Pantazi, A.","Yang, L.","Neill, N. J.","Kim, Y. W.","Creighton, C. J.","Verhaak, R. G.","Mills, G. B.","Park, P. J.","Kucherlapati, R.","Scott, K. L."],"key":"RN6110","id":"RN6110","bibbaseid":"lu-villafane-dogruluk-grzeskowiak-kong-tsang-zagorodna-pantazi-etal-engineeringandfunctionalcharacterizationoffusiongenesidentifiesnoveloncogenicdriversofcancer-2017","role":"author","urls":{},"keyword":["Animals Cell Line","Tumor Cell Transformation","Neoplastic/genetics Female Fusion Proteins","bcr-abl/genetics Humans MAP Kinase Signaling System/genetics Mice Mice","Nude Mutagenesis","Site-Directed/methods Neoplasms/*genetics *Oncogene Fusion Oncogene Proteins","Fusion/*genetics Proto-Oncogene Proteins B-raf/genetics"],"metadata":{"authorlinks":{}}},"bibtype":"article","biburl":"https://verhaaklab.com/files/verhaak.bib","dataSources":["iFXeF2qjAL2y5TeTz"],"keywords":["animals cell line","tumor cell transformation","neoplastic/genetics female fusion proteins","bcr-abl/genetics humans map kinase signaling system/genetics mice mice","nude mutagenesis","site-directed/methods neoplasms/*genetics *oncogene fusion oncogene proteins","fusion/*genetics proto-oncogene proteins b-raf/genetics"],"search_terms":["engineering","functional","characterization","fusion","genes","identifies","novel","oncogenic","drivers","cancer","lu","villafane","dogruluk","grzeskowiak","kong","tsang","zagorodna","pantazi","yang","neill","kim","creighton","verhaak","mills","park","kucherlapati","scott"],"title":"Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer","year":2017}