Radiation Biology

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SU_44_2445 - Transgelin-2 Expression Increases Invasion, Proliferation and Radiation Resistance in IDH Wild-Type Gliomas

Sunday, October 21
1:15 PM - 2:45 PM
Location: Innovation Hub, Exhibit Hall 3

Transgelin-2 Expression Increases Invasion, Proliferation and Radiation Resistance in IDH Wild-Type Gliomas
S. Beyer1, E. H. Bell1, J. McElroy2, O. Oehlke3, J. Fleming1, A. Becker1, E. Bassett1, T. Cui1, Y. Guo1, O. Staszewski4, M. Prinz4, A. Grosu3, S. J. Haque1, and A. Chakravarti1; 1Department of Radiation Oncology, Arthur G. James Hospital/Ohio State Comprehensive Cancer Center, Columbus, OH, 2The Ohio State University, Center for Biostatistics, Columbus, OH, 3Department of Radiation Oncology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany, 4Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany

Purpose/Objective(s): Gliomas with wild-type (wt) isocitrate dehydrogenase1/2 (IDH1/2) demonstrate poor response to chemoradiation and worse prognosis compared to IDH1/2-mutant (mut) gliomas. Therefore, identifying novel therapeutic targets for IDH1/2-wt gliomas is paramount. We performed molecular profiling to elucidate signaling mechanisms governing differences in clinical response between IDH1/2-mut and -wt Grade II and III gliomas. We identified transgelin-2 (TAGLN2), an actin polymerizing gene, to be expressed at significantly higher levels in IDH1/2-wt gliomas compared to IDH1/2-mut gliomas. While TAGLN2 expression has been shown to correlate with prognosis in other cancer types, its role in gliomas has not yet been established. We hypothesized that increased TAGLN2 expression contributes to oncogenesis and poor survival in IDH1/2-wt gliomas.

Materials/Methods: The Affymetrix ClariomD array and LIMMA analysis identified genes differentially expressed between IDH1/2-mut (n=51) vs. -wt (n=7) grade II/III gliomas in our institutional cohort. Cox regression analysis identified genes associated with overall survival (OS) in our cohort. Data were compared with the TCGA lower grade glioma cohort (IDH1/2-mut (n=418) vs. -wt (n=95). Mass spectrometry compared protein expression and the Illumina HM-450K array compared promoter methylation among IDH1/2-mut vs. -wt tumors in our cohort. In vitro functional studies confirmed the role of TAGLN2 in invasion, proliferation and radiation response in stably transfected glioma cells and neurospheres.

Results: TAGLN2 mRNA (FDR<0.1) and protein (FDR<0.05) expression were increased in IDH-wt compared to -mut gliomas within our cohort. Increased TAGLN2 mRNA expression in IDH-wt compared to -mut gliomas was validated in the lower grade glioma TCGA cohort (FDR<0.05). TAGLN2 had increased promoter methylation in IDH1/2-mut (FDR<0.05) gliomas, likely contributing to decreased TAGLN2 expression among IDH1/2-mut gliomas. TAGLN2 mRNA expression (median split) was also associated with poor prognosis in both our cohort (HR 3.74, p=0.079) and the TCGA cohort (HR 2.6, p=3.1x10-5). In vitro studies confirmed that shRNA-mediated knock-down of TAGLN2 decreased proliferation, invasion as well as increased radiation sensitivity in glioma cells and neurospheres. Furthermore, TAGLN2 overexpression increased proliferation, invasion and radiation resistance in glioma cells and neurospheres.

Conclusion: Our study suggests that TAGLN2 may serve as a prognostic biomarker in IDH1/2-wt gliomas by contributing to proliferation, invasion, radiation resistance and therefore may contribute to worse clinical outcomes among these patients. Future studies are ongoing to confirm our results in vivo and to determine the potential for TAGLN2 as a therapeutic target in IDH1/2-wt gliomas. Acknowledgments: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01, BTFC, OSU-CCC (all to AC).

Author Disclosure: S. Beyer: None. E.H. Bell: None. J. McElroy: Employee; The Ohio State University. J. Fleming: None. T. Cui: None. O. Staszewski: None. A. Chakravarti: None.

Sasha Beyer, MD, PhD

The Ohio State University

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