Oncogenic Activation of Fibroblast Growth Factor Receptor-3 and RAS Genes as Non-Overlapping Mutual Exclusive Events in Urinary Bladder Cancer

Abstract

<span style="text-decoration: underline;">Background</span>: Urinary bladder cancer is a common malignancy in the West and ranks as the 7th most common cancer in our region of Kashmir, India. <em>FGFR3 </em>mutations are frequent in superficial urothelial carcinoma (UC) differing from the <em>RAS </em>gene mutational pattern. The aim of this study was to analyze the frequency and association of <em>FGFR3 </em>and <em>RAS </em>gene mutations in UC cases. <span style="text-decoration: underline;">Materials and Methods</span>: Paired tumor and adjacent normal tissue specimens of 65 consecutive UC patients were examined. DNA preparations were evaluated for the occurrence of <em>FGFR3 </em>and <em>RAS </em>gene mutations by PCR-SCCP and DNA sequencing. <span style="text-decoration: underline;">Results</span>: Somatic point mutations of <em>FGFR3 </em>were identified in 32.3% (21 of 65). The pattern and distribution were significantly associated with low grade/stage (p<0.05). The overall mutations in exon 1 and 2 in all the forms of <em>RAS </em>genes aggregated to 21.5% and showed no association with any clinic-pathological parameters. In total, 53.8% (35 of 65) of the tumors studied had mutations in either a <em>RAS </em>or <em>FGFR3 </em>gene, but these were totally mutually exclusive in and none of the samples showed both the mutational events in mutually exclusive <em>RAS </em>and <em>FGFR3</em>. <span style="text-decoration: underline;">Conclusions</span>: We conclude that <em>RAS </em>and <em>FGFR3 </em>mutations in UC are mutually exclusive and non-overlapping events which reflect activation of oncogenic pathways through different elements.