NcXHF

APOLO, VOGELZANG, AND THEODORESCU
cently, somatic mutations in the PIK3CA oncogene, which
encodes the catalytic subunit p110 of class-IA PI3 kinase,
were described in 13% to 27% of bladder tumors. 11 These
mutations often coincided with FGFR3 mutations. Mutations
in the RAS oncogenes (HRAS, KRAS, and NRAS) have
also been found in 13% of bladder tumors and in all stages
and grades; they are mutually exclusive with FGFR3 mutations.
Given these fındings, analyzing urine sediment for genetic
mutations may be a promising strategy for noninvasive
detection of bladder cancer.
KEY POINTS
Detection of mutations in genes such as RAS, FGFR3,
PIK3CA, and TP53, and methylation pathways in urine
sediment are promising noninvasive strategies for diagnosis
of bladder cancer.
The EORTC randomized phase III trial did not show a
substantial improvement in overall survival with adjuvant
cisplatin-based chemotherapy. Although the trial was
limited in power, there was a 22% decrease in the risk of
death (p 0.13 trend) and a 55% decrease in the risk of
recurrence.
Cisplatin-based neoadjuvant chemotherapy remains the
standard of care in muscle-invasive bladder cancer.
Immune checkpoint inhibitors have shown efficacy in
pretreated patients with metastatic bladder cancer,
offering new hope for potential therapeutic strategies in
this disease.
Multiple clinical trials are ongoing and in development in all
stages of urothelial carcinoma, testing checkpoint inhibitors
alone or in combination with other active agents that
enhance the immune system.
FGFR3
FGFR3 mutations occur in around 50% of both lower and
upper urinary tract tumors, clustering in three distinct hotspots
in exons 7, 10, and 15. 12 The most common mutations
in exon 7 and 10 favor ligand-independent dimerization,
transactivation, and signaling. 13-17 Mutations in exon 15 are
rare and induce a conformational change in the kinase domain,
resulting in ligand-independent receptor activation
and signaling, as well as FGFR3 cellular localization, with aberrant
endoplasmic reticulum signaling. 18 FGFR3 mutations
are thought to occur early during urothelial transformation,
as they are reported in over 80% of preneoplastic lesions, 13,14
pointing to an overall “benign” effect of FGFR3 mutation in
the bladder. 17,19 FGFR3-mutant tumors are more chromosomally
stable than their wild-type counterparts. A mutually
exclusive relationship between FGFR3 mutation and overrepresentation
of 8q was observed in NMIBC. 20 A recent
study found that around 80% of NMIBC and 54% of MIBC
have dysregulated FGFR3 with discordant mutation and protein
expression patterns, suggesting a key role for FGFR3 in
both NMIBC and MIBC, either through mutation, overexpression,
or both. 21 These discrepancies may reflect differential
downstream signaling of wild-type and mutant receptors
or the different molecular pathways instigating the development
of these tumors. The mechanisms driving FGFR3 overexpression
in UC are largely unknown, although a recent
study demonstrated the regulation of FGFR3 expression in
urothelial cells by two microRNAs (miR-99a/100) that are
often downregulated in UC, particularly in low-grade and
low-stage tumors. 22
FGFR3 mutations were among the fırst to be used as urine
biomarkers of recurrent disease, especially low-grade disease,
which is challenging to detect by urine cytology. van Rhijn et al 23
reported that combined microsatellite and FGFR3 mutation
analysis could detect UC in voided urine. FGFR3 mutations
were found in 44% of urothelial tumors (59 tumors), but were
absent in 15 G3 tumors. The sensitivity of microsatellites to detect
cancer in voided urine was lower for tumors harboring
FGFR3 mutations (15 out of 21 tumors; 71%) than for FGFR3
wild-type UC (29 out of 32 tumors; 91%). By including the
FGFR3 mutation, the sensitivity of molecular cytology increased
from 71% to 89% and was superior to the sensitivity of morphologic
cytology (25%) for every clinical subdivision. These fındings
highlighted the potential of molecular biology as an adjunct
to cystoscopy and cytology in informing follow-up care.
HRAS
The HRAS gene, which codes for p21 Ras (or Ras), a small GT-
Pase, was the fırst identifıed human oncogene. It was found in
the T24/EJ urothelial cell line. 24-26 In the normal urothelium,
normal Ras protein diminishes with differentiation, with highest
expression in the basal (progenitor) cells. 27 The role of Ras in
UC is supported by its ability to transform Simian vacuolating
virus 40 (SV40)-immortalized human urothelial cells into invasive
transitional-cell carcinomas. 28,29 In addition, in elegant
transgenic studies, Ras overexpression has been shown to lead to
NMIBC. 30 Ras interacts with Raf, a serine/threonine kinase,
which is activated in tumor cells containing enhanced growth
signaling pathways in both NMIBC, MIBC, and metastatic disease
with subsequent activation of MAPK. 31,32
P53
The p53 tumor suppressor encoded by the TP53 gene located
on chromosome 17p13.1 33 inhibits phase-specifıc cell cycle
progression (G1-S) through transcriptional activation of
p21 WAF1/CIP1 . 34 Most UCs exhibit loss of a single 17p allele.
Additional mutations in the remaining allele can inactivate
TP53, leading to increased nuclear accumulation of the mutant
protein, which has a longer half-life than its wild-type
counterpart. 35 TP53 deletion was correlated with grade and
stage of UC. 36-41 Invasive carcinoma can also progress from
recurrent papillary carcinoma by acquiring additional alterations
in TP53, RB1, PTEN, EGFRs, CCND1, MDM2, or
E2F. 42 In addition, oncogenic HRas has been shown to promote
the malignant potency of UC cells that have acquired
106 2015 ASCO EDUCATIONAL BOOK | asco.org/edbook