Novel gene fusion candidates harbouring protein kinase domains in non-muscle-invasive bladder cancer (NMIBC)


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Anshita Goel1,Douglas G. Ward1,Naheema S. Gordon1,Ben Abbotts1,Nicholas D. James1,Maurice P. Zeegers2,Kk Cheng1,Richard T. Bryan1,Roland Arnold1
1University of Birmingham,2Maastricht University, Maastricht

Abstract

Background

More than 7000 cases of non-muscle-invasive bladder cancer (NMIBC) are diagnosed every year in the UK. There is a high rate of disease recurrence and 10-15% of NMIBCs progress to muscle-invasive disease with poor prognosis. There is an urgent need to identify molecular/genetic biomarkers to stratify patients and identify optimal treatments. Gene fusions have been described as stratifiers in other cancer types. We sought to investigate a cohort of 87 bladder cancer patients using RNA-sequencing to detect gene fusions.‚Äč

Method

We analysed 80 NMIBCs (57 G3, 6 G2, 17 G1) and 7 MIBCs. We used the STAR-fusion pipeline and Kallisto + Pizzly algorithms to detect fusions. We only considered candidates detected by both methods, with sufficient read support, and with fusion junctions at known splice-sites.

Results

We identified 162 fusion events after applying all filtering criteria. After selecting for events with partner genes involved in cancer or signalling related KEGG pathway(s), 23 5prime and 13 3prime genes remained, respectively. Kinases were the most statistically significant protein domains in both sets: Tyr_pkinase, (adjusted p-val. 0.002) and Prot_kinase_core, (adjusted p-val. 0.001) for the 5prime and 3prime gene sets, respectively. Confirming for fusions being in-frame, we found FGFR3--TACC3 and ATG7--RAF1 fusions with the kinase domain retained. The previously reported FGFR3 fusion is seen in one high-grade (G3pT1) NMIBC patient. For the first time in bladder cancer, we report a RAF1 fusion in a patient with a G1pTa NMIBC.

Conclusion

Indicators of disease progression in NMIBC would be hugely beneficial to patients. The implication of the FGFR3--TACC3 fusion, known to have a constitutively active tyrosine kinase domain, in the potential progression of NMIBC warrants further investigation. RAF1 is known to form fusions after oncogenic genomic arrangements. Presence of MAPK pathway activation could indicate susceptibility to targeted therapy.