Discovery and Elucidation of The Fgfr3-Tacc3 Recurrent Fusion In Glioblastoma

<p>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 <em>fibroblast growth factor receptor 3</em> (<em>FGFR3</em>) gene to the<em> transforming coiled-coil containing protein 3 </em>(<em>TACC3</em>) gene in glioblastoma multiforme. The fusion occurred in 8.3% of patient samples, but not in low grade or normal samples. <em>FGFR3-TACC3 </em>produced an in-frame fusion protein that promoted an oncogenic phenotype both <em>in vitro</em> and <em>in vivo. </em>While the fusion was overexpressed and contained the majority of the <em>FGFR3 </em>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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2014

Author dc:creator

• Parker Kerrigan, Brittany C

Contributors dc:contributor

• Wei Zhang, Ph.D.
• Andrew Bean, Ph.D.
• Gregory N. Fuller, M.D., Ph.D.

• cancer
• biology
• fusion
• neuroscience
• glioblastoma
• chemotherapy
• Genomics
• Medicine and Health Sciences
• Other Neuroscience and Neurobiology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/509

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1544