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IBCN Abstracts / Urologic Oncology: Seminars and Original Investigations 35 (2017) 608–621
were outlined by two independent observers. Crypts were counted using
strict criteria and crypt density calculated. Immunohistochemistry was used
to assess cell proliferation (BrdU) and apoptosis (cleaved caspase 3) and
phloxine-tartrazine staining used to assess Paneth cell viability.
Results: A log-linear crypt survival curve was observed with mock
treatment and panobinostat over 10 to 14 Gy. There was no significant
reduction in crypt density with panobinostat þ IR (p ¼ 0.631) compared to
mock þ IR. However, with gemcitabine þ IR, there was a significant
reduction in crypt density at 12 Gy (p ¼ 0.001), similar to that observed
with 14 Gy alone.
Conclusions: The modified crypt assay is a promising method to determine
the effects of chemoradiation combinations on small intestine. We are now
developing a murine intestinal organoid system as an in vitro drug/radiation
testing platform, which might replace the crypt assay.
Shedding light into the role of STAG2 in urothelial bladder cancer
Eleonora Lapi, Catarina P. Santos, Gottfrid Sjödahl, Mattias Höglund,
Ana Losada, Francisco X. Real. Spanish National Cancer Research Centre
(CNIO), Madrid, Spain;, Lund University, Lund, Sweden
Objectives: Understanding the molecular mechanisms underlying
urothelial bladder cancer (UBC) development and progression is crucial
to improve diagnosis and design appropriate therapies. Our laboratory and
others identified recently a new tumor suppressor gene, STAG2, which is
part of the cohesin complex. STAG2 inactivating mutations are more
common in non-aggressive, genomically stable, non muscle-invasive BC.
Interestingly, these findings suggest that STAG2 might contribute to cancer
via different mechanisms than aneuploidy. We have, therefore, set out to
identify such mechanisms.
Methods: We integrated human patients’ data with in vitro experiments and
genetic mouse models. We mined TCGA expression data available from
413 samples of MIBC. Moreover, we analyzed Stag2 expression by
immunohistochemistry in 294 tumors (203 NMI and 91 MI) for which
transcriptome and genomic data are available. We have also used UBC cell
lines, cultures of primary murine urothelial cells, and organoids derived
from a conditional Stag2 knockout mouse model.
Results: STAG2 loss of expression is associated with the luminal subtype
of UBC (UroA and UroB subtypes). Among TCGA MIBC cases, STAG2
mutations are associated with subtypes I and II. Luminal-like/Urothelial
tumors are significantly enriched in the PPARg pathway. In vitro
experiments suggest that STAG2 cooperates with PPARg during
urothelial differentiation and bioinformatic analyses show that the PPARg
binding motif is enriched in Stag2 ChIP-Seq peaks in RT112 UBC cells,
suggesting that STAG2 and PPARg co-regulate target genes. In support of
this notion, co-immunoprecipitation experiments indicate that STAG2 and
PPARg physically interact in normal urothelial cells and their binding is
stabilized upon differentiation. Using global transcriptomic analyses, we
have identified Egfr and the ROS pathway as differentially regulated in
Stag2 knockdown cells, further supporting a mechanistic role of Stag2 in
the tumor phenotype. Experiments using mouse urothelial organoids in
which Stag2 is conditionally inactivated in vitro point to a role of this
protein in the stemness potential of urothelial cells.
Conclusions: Our results support the notion that STAG2 inactivation
contributes to bladder cancer development through the regulation of
stemness, differentiation, and growth factor signalling. These findings
provide the basis for the analysis of the genomic effects of STAG2 loss at
the chromatin level and the identification of specific vulnerabilities.
Non-Coding RNA modulate molecular subtype biology in muscle
invasive bladder cancer (MIBC) and are independently associated
with survival
A. Gordon Robertson, Ewan A. Gibb, Mauro Castro, Benilton de
Sa Carvalho, Jaegil Kim, Hikmat Al-Ahmadie, Joaquim Bellmunt,
Katherine Hoadley, John N. Weinstein, David Kwiatkowski, Seth
P. Lerner, on behalf of The Cancer Genome Atlas Research Network
Bladder Cancer Project
Objectives: We recently reported the updated integrated analysis of MIBC
and described 5 mRNA expression-based molecular subtypes that refined
prior clustering analyses. Here we characterize microRNA (miR) and long
non-coding (lnc) RNA expression patterns and describe how these
modulate and further stratify the mRNA-based subtypes and their
association with survival.
Materials and methods: We calculated expression profiles for 8167
(Ensembl v82) lncRNAs. We extracted lncRNAs that were robustly and
variably expressed, and identified subtypes by unsupervised consensus
clustering. Similarly, we identified subtypes for miRNA-seq 5p and 3p
mature strands, using unsupervised consensus clustering with mature
strands that were robustly and variably expressed.
Results: Four unsupervised lncRNA clusters were associated with purity,
EMT score, CIS gene sets, and 5-year survival (p ¼ 0.015). The lncRNA
clusters were concordant with mRNA subtypes and further discriminated
within them. For example, lncRNA cluster 3 (n ¼ 76), a better-survival
subset of the luminal-papillary subtype, was depleted of TP53 mutations
but enriched in FGRF3 mutations and fusions. It consisted largely of highpurity, papillary histology, and organ-confined cancers. miRNA subtypes
were associated with purity, EMT scores, and 5-year survival (p ¼ 0.002).
They were also concordant with subtypes for mRNA, lncRNA,
hypomethylation, RPPA, and with histological subtype, TNM stage, and
CIS gene sets. miRNA subtype 3 was enriched in lncRNA 3 and showed
the best survival among the 4 subtypes, consistent with low EMT scores
and high miR-200 levels. Multivariate regression analyses identified
lncRNA and miRNA subtypes as independent predictors of survival.
Conclusions: We identify and corroborate distinct miRNA and lncRNA
subtypes for muscle-invasive bladder cancer, and describe a high level
of correlation with mRNA subtypes. Clustering by mRNA, lncRNA,
and miRNA expression converged to identify subsets with differential
epithelial-mesenchymal transition status, CIS scores, histologic features, and
Long-term survival after cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) for patients with peritoneal carcinomatosis of urachal cancer
Laura S. Mertens, Mark A. Behrendt, Akash M. Mehta, Jeroen de Jong,
Henk Boot, Laura Stokkel, Michiel S. van der Heijden, Simon Horenblas,
Luc M. Moonen, Vic J. Verwaal, Wim Meinhardt, Bas W.G. van Rhijn.
Department of Urology, The Netherlands Cancer Institute, Amsterdam, The
Netherlands;, Department of Surgery, The Netherlands Cancer Institute,
Amsterdam, The Netherlands;, Department of Pathology, The Netherlands
Cancer Institute, Amsterdam, The Netherlands;, Department of
Gastroenterology, The Netherlands Cancer Institute, Amsterdam, The
Netherlands;, Department of Medical Oncology, The Netherlands Cancer
Institute, Amsterdam, The Netherlands;, Department of Radiation
Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
Objective: Urachal adenocarcinoma (UrAC) is a rare urologic malignancy
arising from urachal remnants at the bladder dome, which can cause peritoneal
carcinomatosis (PC); evidence supporting curative treatment of this aggressive
presentation is lacking. Cytoreductive surgery (CRS) plus hyperthermic
intraperitoneal chemotherapy (HIPEC) is considered the best treatment of
peritoneal carcinomatosis (PC) of several enteric malignancies. We investigated
the long-term oncological outcome after CRS/HIPEC for PC of UrAC.
Material and methods: We identified 48 patients with UrAC treated at our
hospital between 1994-2014. Patients were staged with CT and bonescan or
PET/CT. From 2001 on, all cN0M0 patients underwent staging
laparoscopy. Nine had PC and were treated with CRS/HIPEC; 28 showed
no metastases and underwent local treatment; 11 had distant metastases and
received palliative chemotherapy.
Disease-specific survival (DSS) rates were estimated using the KaplanMeier method and log-rank tests. Postoperative complications represent a
secondary outcome.
Results and limitation: The median follow up was 74 months. Of the CRS/
HIPEC patients, 4 (44.4%) developed a recurrence; 3 (33.3%) died of
disease. The 2-yr and 5-yr DSS were 75% and 63%, respectively. DSS did
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2017, 025, urolonc
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