FGFR3 is frequently activated by mutation in urothelial carcinoma of the bladder. We demonstrate here a further method of activation, by gene fusion following chromosomal re-arrangement. Four fusions with transforming acid coiled-coil 3 (TACC3) resulting from 4p16.3 re-arrangement were identified. A fifth fusion following t(4;7) was with BAI1-associated protein 2-like 1 (BAIAP2L1), also known as IRTKS (Insulin Receptor Kinase Substrate) on chromosome 7. The FGFR3-TACC3 fusions involve four different genomic re-arrangements resulting in three different transcripts. The fusion proteins show constitutive phosphorylation, activation of the MAPK pathway and transform NIH-3T3 cells. All have lost the final exon of FGFR3, which includes the PLCγ1 binding site. Thus PLCγ1 pathway activation and known PLCγ1-induced effects in normal urothelial cells were not induced. The FGFR3-BAIAP2L1 fusion retains most of BAIAP2L1 including the IRSp53/MIM domain (IMD) that mediates actin binding and Rac interaction, while the FGFR3-TACC3 fusions all retain the TACC domain that mediates microtubule binding. As cells containing these fusion genes are highly sensitive to FGFR-selective agents, detection of fusion genes may be useful in selecting patients for targeted therapy.

Citation Format: Sarah V. Williams, Carolyn D. Hurst, Margaret A. Knowles. Activation of FGFR3 by genomic fusion in urothelial carcinoma of the bladder. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5310. doi:10.1158/1538-7445.AM2013-5310