Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling.
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ABSTRACT:
SUBMITTER: Robinson BD
PROVIDER: S-EPMC6611775 | biostudies-literature | 2019 Jul
REPOSITORIES: biostudies-literature
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Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling.
Robinson Brian D BD Vlachostergios Panagiotis J PJ Bhinder Bhavneet B Liu Weisi W Li Kailyn K Moss Tyler J TJ Bareja Rohan R Park Kyung K Tavassoli Peyman P Cyrta Joanna J Tagawa Scott T ST Nanus David M DM Beltran Himisha H Molina Ana M AM Khani Francesca F Miguel Mosquera Juan J Xylinas Evanguelos E Shariat Shahrokh F SF Scherr Douglas S DS Rubin Mark A MA Lerner Seth P SP Matin Surena F SF Elemento Olivier O Faltas Bishoy M BM
Nature communications 20190705 1
Upper tract urothelial carcinoma (UTUC) is characterized by a distinctly aggressive clinical phenotype. To define the biological features driving this phenotype, we performed an integrated analysis of whole-exome and RNA sequencing of UTUC. Here we report several key insights from our molecular dissection of this disease: 1) Most UTUCs are luminal-papillary; 2) UTUC has a T-cell depleted immune contexture; 3) High FGFR3 expression is enriched in UTUC and correlates with its T-cell depleted immun ...[more]
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Project description:Most upper tract urothelial carcinomas (UTUC) are muscle invasive at the time of diagnosis. Current standard methods for the diagnosis of UTUC are invasive. Urine cytology is the only non-invasive test for detecting UTUC, but its sensitivity is low. A novel non-invasive assay for UTUC detection would improve patient outcome. This study aimed to investigate the mutation of cell-free DNA (cfDNA) in urine supernatant to develop a reliable diagnostic biomarker for UTUC patients. We studied urinary cfDNA from 153 individuals, including 56 patients with localized UTUC, and carried out droplet digital PCR assay for TERT promoter and FGFR3 hotspot mutations. We could detect mutations of TERT C228T in 22/56 (39.3%), TERT C250T in 4/56 (7.1%), and FGFR3 S249C in 9/56 (16.1%) patients. FGFR3 mutation was detected only in ?pT1 tumors (positive predictive value: 100.0%). In combination with cytology results, the sensitivity was 78.6%, and the specificity was 96.0%. Although these data need to be validated in a larger-scale cohort, mutation analysis of TERT promoter and FGFR3 in urinary cfDNA has the potential to be a non-invasive diagnostic marker and reliable factor for tumor staging.
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Project description:Upper tract urothelial cancer (UTUC) is a less common disease in Western countries but has a high level of prevalence in Asian populations. Compared to bladder cancer, unique etiologic and genomic factors are involved in UTUC. Fibroblast growth factor receptor 3 (FGFR3) up-regulation has been proposed as a promising target for bladder cancer therapy. In this study, we aimed to profile the expression of FGFR3 in Asian and Caucasian UTUC tissues and to evaluate the in vitro therapeutic efficacy of small interference RNA (siRNA)-mediated FGFR3 silencing in UTUC treatment. The FGFR3 expression levels in renal pelvis tissues and microarray sections from Asian and Caucasian patients with UTUC, respectively, were measured via immunohistochemistry. The BFTC-909 and UM-UC-14 UTUC cell lines were used to examine the effects of FGFR3 silencing on proliferation, migration, epithelial-mesenchymal transition (EMT) marker expression, and signaling machinery. FGFR3 expression increased as the TNM stage increased in both Asian and Caucasian UTUC tumors, and no statistical difference was identified between the two groups. In vitro studies demonstrated that FGFR3 siRNA delivery significantly inhibited proliferation and migration and suppressed the expression of EMT markers and transcription factors in UTUC cells. Mechanistically, FGFR3 silencing alleviated the constitutive expression of RAS and the phosphorylation of MAPK signaling mediators, including ERK1/2 and JNK1/2. FGFR3 silencing elicited an apoptosis-inducing effect similar to that of FGFR inhibition. Conclusion: siRNA-targeted FGFR3 expression may impede the expansion and invasion of UTUC cells by alleviating the RAS/MAPK signaling pathway. The genetic interference of FGFR3 expression via siRNA in UTUC cells may constitute a useful therapeutic strategy.
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Project description:Despite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences.To investigate whether the differences between UTUC and UCB result from intrinsic biological diversity.Tumor and germline DNA from patients with UTUC (n=83) and UCB (n=102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes.We described co-mutation patterns and copy number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n=59) and high-grade UCB (n=102).Comparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed.High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma.Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.
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Project description:Immunohistochemical (IHC) staining for CK5/6 and CK20 was reported to be correlated with the prognosis of early urothelial carcinoma in a way contrary to that of advanced tumors for unknown reasons. We aimed to characterize the gene expression profiles of subgroups of non-muscle-invasive papillary high-grade upper tract urothelial carcinoma (UTUC) classified by CK5/6 and CK20 expression levels: group 1 (CK5/6-high/CK20-low), group 2 (CK5/6-high/CK20-high), and group 3 (CK5/6-low/CK20-high). Expression of group 3 was predictive of worse prognosis of non-muscle-invasive papillary high-grade UTUC. Transcriptional analysis revealed 308 differentially expressed genes across the subgroups. Functional analyses of the genes identified cell adhesion as a common process differentially enriched in group 3 compared to the other groups, which could explain its high-risk phenotype. Late cell cycle/proliferation signatures were also enriched in group 3 and in some of the other groups, which may be used as a prognostic biomarker complementary to CK5/6 and CK20. Group 2, characterized by low levels of genes associated with mitogen-activated protein kinase and tumor necrosis factor signaling pathways, was hypothesized to represent the least cancerous subtype considering its normal urothelium-like IHC pattern. This study would facilitate the application of easily accessible prognostic biomarkers in practice.
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Project description:Object: CK14 expression is an important marker of basal/squamous-like (BASQ)-type muscle-invasive bladder carcinoma, and this molecularly defined subtype has a poor prognosis and a distinct response to chemotherapy. However, CK14 expression and its clinicopathological and molecular significance in papillary non-muscle-invasive upper tract urothelial carcinoma (NMIUTUC) remain unknown. Herein, we investigated the prognostic implications of immunohistochemical (IHC) staining for CK14 and the transcriptional characteristics associated with CK14 expression in papillary NMIUTUC. Materials and Methods: IHC staining for CK14 was conducted in 204 papillary NMIUTUC specimens. Positive CK14 IHC staining was defined as a positive signal in >0% of tumor cells. RNA sequencing data were analyzed from 8 papillary high-grade NMIUTUC specimens consisting of 4 CK14-positive and 4 CK14-negative tumors. Results: CK14 positivity was associated with a high TNM stage (p < 0.001) and a high World Health Organization grade (p = 0.003). Survival analysis showed that CK14 positivity was significantly associated with poor progression-free survival (p = 0.015; hazard ratio [HR] = 2.990; 95% confidence interval [CI] = 1.180-7.580) and was marginally associated with poor cancer-specific survival (p = 0.052; HR = 3.77; 95% CI = 0.900-15.780). Gene set enrichment analysis demonstrated that the CK14-positive tumors were associated with a basal subtype of breast cancer, squamous cell carcinoma development, p40, tumor necrosis factor α-nuclear factor-κB, and p53 pathways, and embryonic stem cells; these characteristics are reminiscent of the BASQ subtype. In addition, with a p < 0.05 and |fold change| ≥2 as the cutoffs, we identified 178 differentially expressed genes when comparing CK14-positive and CK14-negative tumors. Functional analysis of these genes revealed several networks and gene ontology terms related to the positive regulation of cellular proliferation in CK14-positive tumors. Consistent with these results, we demonstrated that the mean Ki-67 proliferative index was higher in CK14-positive tumors than it was in CK14-negative tumors (2.3 vs. 0.8%, respectively, p = 0.002). Conclusion: CK14-positive papillary NMIUTUC is an aggressive subtype with BASQ-like molecular characteristics and dynamic proliferative activity. We propose that CK14 IHC staining can be a useful biomarker of BASQ-type papillary NMIUTUC that can be applied in daily practice with the aim of precision oncology.
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Project description:Urothelial carcinoma is a highly heterogeneous disease that can arise throughout the entire urothelial lining from the renal pelvis to the proximal urethra. Upper tract urothelial carcinoma (UTUC) is rare, and while it shares many similarities with urothelial carcinoma of bladder (UCB), there are also significant differences between UTUC and UCB regarding clinical management and outcomes. No major advances have been made recently in the development of new systemic therapies for urothelial carcinoma, partly due to the lack of understanding of underlying molecular pathogenetic mechanisms. In the past decade, the emergence of next-generation sequencing has greatly enabled genomic characterization of tumor samples. Researchers are currently exploring a personalized approach to augment traditional clinical decision-making based on genetic alterations. In the present review, we summarize current genomic advances in UTUC and discuss the potential implications of these developments for developing prognostic and predictive biomarkers.
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Project description:PurposeMicropapillary variant upper tract urothelial cancer (MP-UTUC) is a rare malignancy with little known regarding its clinical course and/or optimal treatment. In this case series, we describe patient characteristics, surgical treatment, oncologic outcomes, and response to perioperative chemotherapy.Materials and methodsWe conducted a review to identify patients with MP-UTUC treated at our center between January 1994 and October 2017. Clinicopathologic data was obtained. Descriptive statistics, Kaplan-Meier analysis, Cox proportional hazards, and nearest neighbor matching were used to examine the cohort.ResultsEighteen, (4.3%) of 416 patients were found to have MP-UTUC at our institution over a 23-year period. The majority of patients had ≥pT3 disease at the time of extirpative surgery (13/18, 72%) and one was identified as MP-UTUC prior to surgery. Seven patients received neoadjuvant chemotherapy and six patients received adjuvant chemotherapy. Median overall, cancer specific, and recurrence free survival were 3.29, 3.29, and 1.69 years, respectively for MP-UTUC. There was no survival difference between conventional UTUC and MP-UTUC when matched for age, stage, grade, lymphovascular invasion, and margins (HR 1.18, P = 0.567). No MP-UTUC patients receiving neoadjuvant and adjuvant chemotherapy had apparent pathologic down staging, and of those receiving adjuvant chemotherapy two-thirds died of disease within 2 years.ConclusionsMP-UTUC is a rare, and in most cases aggressive malignancy that commonly presents as locally advanced disease. In this case series, MP-UTUC does not appear to respond to perioperative chemotherapy as neoadjuvant and adjuvant chemotherapy did not result in apparent pathologic down staging and the majority of those receiving adjuvant chemotherapy died from MP-UTUC.
| S-EPMC6511295 | biostudies-literature
Project description:IntroductionUpper tract urothelial carcinoma (UTUC) is a relatively uncommon urologic malignancy for which there has not been significant improvement in survival over the past few decades, highlighting the need for optimal multi-modality management.MethodsA non-systematic review of the latest literature was performed to include relevant articles up to June 2019. It summarizes the epidemiologic risk factors associated with UTUC, including smoking, carcinogenic aromatic amines, arsenic, aristolochic acid, and Lynch syndrome. Molecular pathways underlying UTUC and potential druggable targets are outlined.ResultsSurgical management for UTUC includes kidney-sparing surgery (KSS) for low-risk disease and radical nephroureterectomy (RNU) for high-risk disease. Endoscopic management of UTUC may include ureteroscopic or percutaneous resection. Topical instillation therapy post-KSS aims to reduce recurrence, progression and to treat carcinoma-in-situ; this may be achieved retrogradely (via ureteric catheterization), antegradely (via percutaneous nephrostomy) or via reflux through double-J stent. RNU, which may be performed via open, laparoscopic or robot-assisted approaches, is the gold standard treatment for high-risk UTUC. The distal cuff may be dealt with extravesical, transvesical or endoscopic techniques. Peri-operative chemotherapy and immunotherapy are increasingly utilized; level 1 evidence exists for adjuvant chemotherapy, but neoadjuvant chemotherapy is favored as kidney function is better prior to RNU. Immunotherapy is primarily reserved for metastatic UTUC but is currently being investigated in the perioperative setting.ConclusionThe optimal management of UTUC includes a firm understanding of the epidemiological factors and molecular pathways. Surgical management includes KSS for low-risk disease and RNU for high-risk disease. Peri-operative immunotherapy and chemotherapy may be considered as evidence mounts.
| S-EPMC6954076 | biostudies-literature
Project description:While radical nephroureterectomy (RNU) remains the gold-standard treatment for upper tract urothelial carcinoma (UTUC), a growing volume of literature surrounding endoscopic, organ-sparing procedures has developed over the past few decades. Based on this, endoscopic management of UTUC has gained acceptance as a standard of care approach, particularly among those with low-risk disease or with imperative indications for organ preservation. As a rare disease, however, data is mostly restricted to retrospective single institution series with relatively small numbers. Therefore, comparative outcomes of endoscopic management to RNU remain incompletely defined. Furthermore, the comparative utility of endoscopic approaches (ureteroscopy versus percutaneous resection) and topical therapy following resection lacks prospective analysis. In this article we review the available literature on endoscopic management of UTUC.
| S-EPMC7475653 | biostudies-literature
Project description:BackgroundUpper tract urothelial carcinoma (UTUC) is a rare malignancy. The management of metastatic or unresectable UTUC is mainly based on evidence extrapolated from histologically homologous bladder cancer, including platinum-based chemotherapy and immune checkpoint inhibitor alone, whereas UTUC exhibits more invasiveness, worse prognosis, and comparatively inferior response to treatments. First-line immunochemotherapy regimens have been attempted in clinical trials for unselected naïve-treated cases, but their efficacies relative to standard chemo- or immuno-monotherapy still remain controversial. Here, we present a case of highly aggressive UTUC for whom comprehensive genetic and phenotypic signatures predicted sustained complete response to first-line immunochemotherapy.Case presentationA 50-year-old man received retroperitoneoscopic nephroureterectomy and regional lymphadenectomy for high-risk locally advanced UTUC. Postoperatively, he developed rapid progression of residual unresectable metastatic lymph nodes. Pathologic analysis and next-generation sequencing classified the tumor as highly aggressive TP53/MDM2-mutated subtype with features more than expression of programmed death ligand-1, including ERBB2 mutations, luminal immune-infiltrated contexture, and non-mesenchymal state. Immunochemotherapy combining gemcitabine, carboplatin, and off-label programmed death-1 inhibitor sintilimab was initiated, and sintilimab monotherapy was maintained up to 1 year. Retroperitoneal lymphatic metastases gradually regressed to complete response. Blood-based analyses were performed longitudinally for serum tumor markers, inflammatory parameters, peripheral immune cells, and circulating tumor DNA (ctDNA) profiling. The ctDNA kinetics of tumor mutation burden and mean variant allele frequency accurately predicted postoperative progression and sustained response to the following immunochemotherapy, which were mirrored by dynamic changes in abundances of ctDNA mutations from UTUC-typical variant genes. The patient remained free of recurrence or metastasis as of this publishing, over 2 years after the initial surgical treatment.ConclusionImmunochemotherapy may be a promising first-line option for advanced or metastatic UTUC selected with specific genomic or phenotypic signatures, and blood-based analyses incorporating ctDNA profiling provide precise longitudinal monitoring.
| S-EPMC10328386 | biostudies-literature