Discovery And Elucidation Of The Fgfr3-Tacc3 Recurrent Fusion In Glioblastoma

Author

Brittany C. Parker Kerrigan, The University of Texas Graduate School of Biomedical Sciences at HoustonFollow

Date of Graduation

8-2014

Document Type

Dissertation (PhD)

Program Affiliation

Neuroscience

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Wei Zhang, Ph.D.

Committee Member

Andrew Bean, Ph.D.

Committee Member

Gregory N. Fuller, M.D., Ph.D.

Committee Member

Frederick F. Lang, M.D.

Committee Member

Kartik Venkatachalam, Ph.D.

Abstract

Fusion genes occur due to chromosomal instability where two previously separate genes rearrange and fuse together, forming a hybrid gene. The first fusions were reported in leukemias; however, with the advent of more powerful sequencing technologies, fusions have recently been reported in several solid tumors. Using next-generation deep sequencing approaches, we discovered a fusion gene connecting the fibroblast growth factor receptor 3 (FGFR3) gene to the transforming coiled-coil containing protein 3 (TACC3) gene in glioblastoma multiforme. The fusion occurred in 8.3% of patient samples, but not in low grade or normal samples. FGFR3-TACC3 produced an in-frame fusion protein that promoted an oncogenic phenotype both in vitro and in vivo. While the fusion was overexpressed and contained the majority of the FGFR3 gene, levels of wild-type FGFR3 were very low. We attributed this effect to the ability of the fusion to bypass miR-99a regulation, by losing the 3’ UTR of FGFR3 upon formation of the fusion. The fusion activated ERK and STAT3 signaling, and was more sensitive to FGFR, ERK, and STAT3 inhibitors, while more resistant to treatment with frontline chemotherapy agent, temozolomide.

Keywords

cancer, biology, fusion, neuroscience, glioblastoma, chemotherapy