Clinically advanced urothelial bladder cancer (CAUBC) in young onset bladder cancer (YOUC) patients: A genomic landscape study.
Authors: Basnet Alina , Kamat Ashish M. , Necchi Andrea , Li Roger , Spiess Philippe E. , Grivas Petros , Agarwal Neeraj , Cheng Liang , Pavlick Dean , Ross Jeffrey S. , Lin Douglas I , Gjoerup Ole , Jacob Joseph M , Jamaspishvili Tamara , Bratslavsky Gennady , Gupta Shilpa 
Published: February 2025

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Background:
CAUBC (any patients with node positive, metastasis positive or inoperable T4 disease) arising in YOUC is a challenging disease with significant need for improvements in systemic therapy especially for patients with surgically incurable disease.
Methods:
9,411 cases of CAUBC underwent comprehensive genomic profiling (CGP) to examine all classes of genomic alterations (GA). MSI high status, tumor mutation burden (TMB) levels, genomic ancestry and trinucleotide mutational signatures were determined from the sequencing data. HRDsig status was calculated using a broad set of genome-wide copy number features (PMID 37769224). PD-L1 was determined by IHC using the Dako 22C3 tumor proportional score (TPS) system. Results were compared using the Fisher exact system with the Benjamini-Hochberg adjustment to correct for false discovery.
Results:
291 (3.1%) CAUBC developed in YOUC patients under the age of 50 (CAUBC<50). The GA and biomarkers were compared with 9,120 CAUBC that developed in patients 50 years of age and older (CAUBC>50). The male gender preponderance in the CAUBC>50 was greater than in the CAUBC<50 cases (75.1% vs 69.4%; p=.069). The GA/tumor were higher in the CAUBC>50 (8.0 vs 7.0; p<.0001). Genomic ancestry distribution revealed significantly more Admixed American cases in the CAUBC<50 (8.9% vs 5.2%; P=.033) and more European cases in the CAUBC>50 (85.3% vs 74.9%; P<.0001). MSI high status was extremely uncommon (range 0.3% to 0.8%; NS). The frequency of TMB > 10 mutations/Mb was higher in the CAUBC>50 patients (35.1% vs 28.5%; P=.048). An APOBEC trinucleotide signature was more frequent in the CAUBC>50 patients (32.5% vs 25.8%; p=.041). PD-L1 low expression (1-49% TPS) was available in small subsets of cases and was similar in both groups (21.5% vs 28.5%; p=.84). GA in KMD6A (26.6% vs 14.8%; p=.0001),
ERBB2
(18.4% vs 16.8%; p=.85.),
ERBB3
(6.3% vs 6.5%; p=.91)
MTAP
(25.0% vs 20.3%; p=.27) and
TERT
(78.0% vs 68.4%; p=.005) were more frequent in CAUBC>50 cases and GA in
HRAS
(4.8% vs 2.1%; p=.11) and CCND1 (16.2% vs 13.1%; p=.35) were more frequent in the CAUBC<50 cases. GA in
FGFR1
(4.1% vs 5.2%; p=.71),
FGFR3
(14.1% vs 17.9%; p=.31),
PIK3CA
(20.3% vs 21.3%; p=.91) and
PTEN
(6.5% vs 4.5%; p=.31) were similar in both groups.
Conclusions:
In review of the CGP data, in contrast with CAUBC arising in older patients > 50 years of age, CAUBC arising in YOUC patients <50 years features a unique patten of biomarker and GA distribution that has potential to influence therapy selection and guide future clinical trials.

CAUBC 0-49 years
CAUBC >50 years
P-value

Sex (% male)
69.4%
75.1%
.069

AMR ancestry
8.9%
5.2%
.033

EUR ancestry
74.9%
85.3%
<.0001

FGFR3

14.1%
17.9%
NS

KDM6A

14.8%
26.6%
.0001

MTAP

20.3%
25.0%
NS

TERT

68.4%
78.0%
.005

TMB>10 mut/Mb
28.5%
35.1%
.048

APOBEC Signature
25.8%
32.5%
.041