Prevalence of FGFR3 p.Arg248Cys mutation in lynch syndrome associated urothelial carcinoma: A single institution dataset.
Authors: Rametta Alessandro , Vitellaro Marco , Barella Marco , Stellato Marco , Ambrosini Paolo , Guadalupi Valentina , Nazzani Sebastiano , Biasoni Davide , Catanzaro Mario , Scardino Andrea , Paolini Biagio , Vingiani Andrea , Perrone Federica , Tamborini Elena , Barbetta Francesca , Nicolai Nicola , Pruneri Giancarlo , Milione Massimo , Procopio Giuseppe , Giannatempo Patrizia 
Published: February 2025

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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>T
PIK3CA, TP53, RB1
pT1e
NX
HG

5

F
MSH2
Renal Pelvis
FGFR3 c.742C>T
PIK3CA
Ta
NX
LG

6

F
MSH6
Bladder
-
TP53
T1
NX
HG

7

M
MLH1
Ureter
FGFR3 c.742C>T
-
T2
N1
HG

8

F
MSH2
Renal Pelvis
FGFR3 c.742C>T
ARID1A
T3
N2
HG

9

F
MSH6
Bladder
x
x
T1
NX
HG

10

M
MSH2
Bladder
x
x
T1
NX
HG

11

F
MSH2
Renal Pelvis
-
MSH2, BARD1, NF1, SMARCA4
T4
N0
HG

12

M
MSH6
Ureter
FGFR3 c.742C>T
PIK3CA
T1
N0
HG

13

M
MLH1
Ureter
-
FBXW7, PTPN11
x
x
x