Prevalence of FGFR3 p.Arg248Cys mutation in lynch syndrome associated urothelial carcinoma: A single institution dataset.

858 Background: Patients with Lynch syndrome have an increased risk of developing UC and a relative risk in patient with MSH2 germline impairment of 3,6. In 2024, kinase-inhibitor erdafinitib has been approved in FGFR3 mutated locally advanced and metastatic UC. The aim of the study is to molecularly characterize Lynch-syndrome associated UC (LS-UC). Methods: Starting from a single-institution dataset of patients with Lynch syndrome, we identified 24 patients with LS-UC, of which 13 cases had available specimen for molecular analysis. A DNA NGS analysis was performed with a Cancer Hot-Spot Panel (Thermo Fisher Scientific) covering 50 genes, the detection of fusion transcripts was carried out by RNA-based Oncomine Comprehensive Assay Plus (Thermo Fisher Scientific). Specimen, which didn’t pass internal quality control, were excluded. Results: Our case set was composed of 4 (31%) renal pelvis UC, 4 (31%) ureter UC and 5 (38%) bladder UC and germline pathogenetic variant (GPV) was detected in MSH2 in 7/13 (54%) patients, in MSH6 in 4/13 and in MLH1 in 2/13. Nine specimen provided evaluable material for molecular analysis. No gene fusions were detected in examined genes. The most frequent altered gene was FGFR3 in 6 (46%) cases. In one case, p.Glu368Lys mutation was observed, which is classified as variant of uncertain significance. In five cases (38%), we found the pathogenic variant p.Arg248Cys, which is set near the most frequent alteration in FGFR3 gene in sporadic UC (p.Ser249Cys) and is associated with a good response to erdafinitib. No differences were observed between cases with pathogenic FGFR3 mutation and other cases in term of GPV, tumor site, histologic grade and relapse. Among p.Arg248Cys FGFR3 mutated UC, 4/5 were upper tract UC and 1/4 was bladder UC, four carcinomas were high grade and one was low grade. At surgery time, 2/5 were locally advance with lymph node metastasis and both had a lymph node relapse within 24 months. Conclusions: Despite the small sample size, we confirmed a prominent relation between MSH2 germline mutation and the development of UC. Moreover, we observed a clear preponderance of p.Arg248Cys mutation in FGFR3 mutated LS-UC. These data shine a spotlight on druggable mutation in LS-UC, suggesting a role for molecular analysis in the therapeutic algorithm of these patients. Case Sex Pathogenic Variant Site FGFR3 mutation Other Pathogenic Mutation T N Grade 1 F MSH2 Renal Pelvis x x T1 NX LG 2 M MSH6 Bladder x x Ta NX LG 3 M MSH2 Ureter FGFR3 p.Glu368Lys (VUS) SMARCB1 T3 N0 HG 4 F MSH2 Bladder FGFR3 c.742C&gt;T PIK3CA, TP53, RB1 pT1e NX HG 5 F MSH2 Renal Pelvis FGFR3 c.742C&gt;T PIK3CA Ta NX LG 6 F MSH6 Bladder - TP53 T1 NX HG 7 M MLH1 Ureter FGFR3 c.742C&gt;T - T2 N1 HG 8</j