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Therapeutics, Targets, and Chemical Biology

Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer

Hengyu Lu, Nicole Villafane, Turgut Dogruluk, Caitlin L. Grzeskowiak, Kathleen Kong, Yiu Huen Tsang, Oksana Zagorodna, Angeliki Pantazi, Lixing Yang, Nicholas J. Neill, Young Won Kim, Chad J. Creighton, Roel G. Verhaak, Gordon B. Mills, Peter J. Park, Raju Kucherlapati and Kenneth L. Scott
Hengyu Lu
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
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Nicole Villafane
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
2Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas.
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Turgut Dogruluk
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
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Caitlin L. Grzeskowiak
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
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Kathleen Kong
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
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Yiu Huen Tsang
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
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Oksana Zagorodna
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
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Angeliki Pantazi
3Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts.
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Lixing Yang
4Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts.
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Nicholas J. Neill
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
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Young Won Kim
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
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Chad J. Creighton
5Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
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Roel G. Verhaak
6The Jackson Laboratory, Genomic Medicine, Farmington, Connecticut.
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Gordon B. Mills
7Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas.
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Peter J. Park
3Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts.
4Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts.
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Raju Kucherlapati
3Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts.
8Department of Genetics, Harvard Medical School, Boston, Massachusetts.
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Kenneth L. Scott
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
5Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
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  • For correspondence: kls1@bcm.edu
DOI: 10.1158/0008-5472.CAN-16-2745 Published July 2017
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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.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Received October 14, 2016.
  • Revision received March 7, 2017.
  • Accepted April 27, 2017.
  • ©2017 American Association for Cancer Research.
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Cancer Research: 77 (13)
July 2017
Volume 77, Issue 13
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Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer
Hengyu Lu, Nicole Villafane, Turgut Dogruluk, Caitlin L. Grzeskowiak, Kathleen Kong, Yiu Huen Tsang, Oksana Zagorodna, Angeliki Pantazi, Lixing Yang, Nicholas J. Neill, Young Won Kim, Chad J. Creighton, Roel G. Verhaak, Gordon B. Mills, Peter J. Park, Raju Kucherlapati and Kenneth L. Scott
Cancer Res July 1 2017 (77) (13) 3502-3512; DOI: 10.1158/0008-5472.CAN-16-2745

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Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer
Hengyu Lu, Nicole Villafane, Turgut Dogruluk, Caitlin L. Grzeskowiak, Kathleen Kong, Yiu Huen Tsang, Oksana Zagorodna, Angeliki Pantazi, Lixing Yang, Nicholas J. Neill, Young Won Kim, Chad J. Creighton, Roel G. Verhaak, Gordon B. Mills, Peter J. Park, Raju Kucherlapati and Kenneth L. Scott
Cancer Res July 1 2017 (77) (13) 3502-3512; DOI: 10.1158/0008-5472.CAN-16-2745
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