EURURO Vol. 72 No. 6

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3.2. Genomic landscape of NMIBC
The most frequently altered genes in NMIBC were the TERT
promoter (73%), FGFR3 (49%), KDM6A (38%), PIK3CA (26%),
STAG2 (23%), ARID1A (21%), and TP53 (21%)
Supplementary Figs. 2 and 3, Supplementary Table 4).
The associations between genetic alterations with tumor
stage and grade are presented in Supplementary
Tables 5 and 6. TERT promoter mutations were identified
in 61% (14/23) of LGTa, 88% (28/32) of HGTa, and 79% (30/
38) of HGT1 tumors. The TERT promoter region was not
sequenced by TCGA, as the whole-exome sequencing
method employed interrogated only protein-coding
regions. However, TERTpromoter mutations were identified
in 85% (34/40) of the MSK-MIBC patients. TERT promoter
mutations were present at similar frequency across stage
(p = 0.2) and grade (p = 0.15).
Alterations in chromatin modifying genes were also
highly prevalent in NMIBC, occurring in 69% (72/105) of the
tumors , Supplementary Fig. 4). The most commonly
altered chromatin-modifying genes were KDM6A (38%) and
ARID1A (21%). KDM6A was altered in 52% (12/23) of LGTa,
38% of HGTa (12/32), 32% (12/38) of HGT1, and 25% (10/40)
of MSK-MIBC, and 24% of TCGA-MIBC tumors. ARID1A
mutations were identified in 9% (2/23) of LGTa, 28% (9/32)
of HGTa, 18% (7/38) of HGT1, 30% (12/40) of MSK-MIBC, and
24% of TCGA-MIBC tumors. While KDM6A alterations were
identified more often in LGTa, there were no statistically
significant associations with grade (p = 0.15) or stage
(p = 0.44). Similarly, ARID1A mutation did not correlate
with either grade (p = 0.23) or stage (p = 0.44).
Another frequently altered gene was STAG2, present in
23% of the NMIBC cohort (LGTa = 39% [9/23]; HGTa = 16%
[5/32]; HGT1 = 24% [9/380], 5% of MSK-MIBC [2/40], and
15% of TCGA-MIBC; . Studies are conflicted over
whether STAG2 mutations are associated with aneuploidy
and aggressive bladder tumors or associated with lower
grade and l-stage disease We found truncat-
ing STAG2 mutations in our cohort to be associated with
LGTa tumors (p = 0.046).
3.3. Genomic pathways of NMIBC
To better define the prevalence and co-occurrence patterns
of potentially actionable genomic alterations in NMIBC, we
analyzed known cancer-associated genes within the context
of their canonical pathway and cellular function. Alterations
in the receptor tyrosine kinase/phosphatidylinositol
3-kinase pathway were present in 79% (83/105) of NMIBC
tumors Supplementary Fig. 5). Consistent with
previous studies, FGFR3 mutations were associated with
lower grade and stage (LGTa = 83% [19/23]; HGTa = 59% [19/
32]; HGT1 = 34% [13/38]; MSK-MIBC = 8% [3/40]; TCGA-
MIBC = 16%) . Four FGFR3 fusions were identified in the
NMIBC cohort, including a FGFR3-TNIP2 fusion predicted to
be activating due to its in-frame FGFR3 kinase domain and a
recent NGS report identifying another bladder tumor with a
FGFR3-TNIP2 fusion We also identified a FGFR3-TACC3
fusion in a LGTa tumor. While FGFR3 fusions have
predominantly been reported only in high-grade tumors,
there are a few low-grade papillary bladder cell lines known
to harbor FGFR3-TACC3 fusions .
Table 1 – Clinicopathologic characteristics of NMIBC cohorts
Characteristics Low-grade
NMIBC (%), n = 23
High-grade
NMIBC (%), n= 82
High-grade NMIBC treated BCG
without maintenance (%), n = 62
Median age (range) 67 (25, 80) 70 (36, 87) 69.8 (37.3, 87.3)
Sex
Male 13 (56) 67 (82) 51 (82)
Female 10 (43) 15 (18) 11 (18)
Smoking
Current 3 (13) 13 (16) 9 (15)
Former 13 (57) 46 (56) 35 (56)
Never 7 (30) 23 (28) 18 (29)
Stage
Ta 23 (100) 32 (39) 26 (42)
Tis 0 12 (15) 12 (19)
T1 0 38 (46) 24 (39)
No. of tumors
Single 18 (78) 45 (55) 33 (53)
Multiple 5 (22) 37 (45) 29 (46)
Tumor size (cm)
<3 16 (70) 46 (56) 36 (58)
3 7 (30) 36 (44) 26 (42)
Concomitant CIS
No 23 (100) 43 (52) 30 (48)
Yes 0 (0) 39 (47) 32 (52)
Treatment
BCG 3 (13) 66 (80) 62 (100)
MMC 9 (39) 1 (1) 0 (0)
Observation 11 (48) 10 (12) 0 (0)
Immediate cystectomy 0 (0) 5 (6) 0 (0)
BCG = bacillus Calmette-Gue´rin; CIS = carcinoma in situ; MMC = mitomycin; MIBC = muscle invasive bladder cancer; NMIBC = nonmuscle invasive bladder
cancer; TUR = transurethral resection.
E U R O P E A N U R O L O G Y 7 2 ( 2 0 1 7 ) 9 5 2 – 9 5 9 954