Dataset Information

Genomic Biomarkers for the Prediction of Stage and Prognosis of Upper Tract Urothelial Carcinoma.

ABSTRACT: Genomic characterization of radical nephroureterectomy specimens in patients with upper tract urothelial carcinoma may allow for thoughtful integration of systemic and targeted therapies. We sought to determine whether genomic alterations in upper tract urothelial carcinoma are associated with adverse pathological and clinical outcomes.Next generation exon capture sequencing of 300 cancer associated genes was performed in 83 patients with upper tract urothelial carcinoma. Genomic alterations were assessed individually and also grouped into core signal transduction pathways or canonical cell functions for association with clinicopathological outcomes. Binary outcomes, including grade (high vs low), T stage (pTa/T1/T2 vs pT3/T4) and organ confined status (pT2 or less and N0/Nx vs greater than pT2 or N+) were assessed with the Kruskal-Wallis and Fisher exact tests as appropriate. Associations between alterations and survival were estimated using the Kaplan-Meier method and Cox regression.Of the 24 most commonly altered genes in 9 pathways TP53/MDM2 alterations and FGFR3 mutations were the only 2 alterations uniformly associated with high grade, advanced stage, nonorgan confined disease, and recurrence-free and cancer specific survival. TP53/MDM2 alterations were associated with adverse clinicopathological outcomes whereas FGFR3 mutations were associated with favorable outcomes. We created a risk score using TP53/MDM2 and FGFR3 status that was able to discriminate between adverse pathological and clinical outcomes, including in the subset of patients with high grade disease. The study is limited by small numbers and lack of validation.Our data indicate that specific genomic alterations in radical nephroureterectomy specimens correlate with tumor grade, stage and cancer specific survival outcomes.

SUBMITTER: Bagrodia A

PROVIDER: S-EPMC4871772 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Genomic Biomarkers for the Prediction of Stage and Prognosis of Upper Tract Urothelial Carcinoma.

Bagrodia Aditya A Cha Eugene K EK Sfakianos John P JP Zabor Emily C EC Bochner Bernard H BH Al-Ahmadie Hikmat A HA Solit David B DB Coleman Jonathan A JA Iyer Gopa G Scott Sasinya N SN Shah Ronak R Ostrovnaya Irina I Lee Byron B Desai Neil B NB Ren Qinghu Q Rosenberg Jonathan E JE Dalbagni Guido G Bajorin Dean F DF Reuter Victor E VE Berger Michael F MF

The Journal of urology 20160114 6

<h4>Purpose</h4>Genomic characterization of radical nephroureterectomy specimens in patients with upper tract urothelial carcinoma may allow for thoughtful integration of systemic and targeted therapies. We sought to determine whether genomic alterations in upper tract urothelial carcinoma are associated with adverse pathological and clinical outcomes.<h4>Materials and methods</h4>Next generation exon capture sequencing of 300 cancer associated genes was performed in 83 patients with upper tract ...[more]

PMID: 26778714

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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.

Project description:BackgroundDifferent genomic characterization in urothelial carcinoma (UC) by site of origin may imply contrasting therapeutic opportunities and pathogenetic mechanisms. The aim of this study was to investigate whether differences between upper tract UC (UTUC) and UC of the bladder (UCB) result from intrinsic biological diversity.Materials and methodsWe prospectively sequenced 118 tumors and matched blood DNA from Chinese patients with UC using next-generation sequencing techniques, including 45 UTUC and 73 UCB. Two hundred twenty-six patients with UTUC and 350 patients with UCB for The Cancer Genome Atlas were acquired from the cbioportal.ResultsThere were marked disparities in the mutational landscape for UC according to race and site of origin. Signature 22 for exposure to aristolochic acid was only observed in the UTUC cohort. Conversely, signature 6 for defective DNA mismatch repair only existed in the UCB cohort. Compared with UCB, UTUC had higher clonal and subclonal mutation numbers. TP53, PIK3CA, and FGFR3 mutations may be the driver genes for UTUC, whereas for UCB, the driver gene may be BRCA1. Patients with UTUC had lower PD-L1 than those with UCB. There was no significant difference in the number of DDR mutations, copy number variation counts, and tumor mutational burden between UTUC and UCB.ConclusionUTUC and UCB exhibit significant differences in the prevalence of genomic landscape and carcinogenesis. Consequently, molecular subtypes differ according to location, and these results may imply the site-specific management of patients with urothelial carcinoma. Mutational signature may be used as a screening tool to assist clinical differential diagnosis between UTUC and UCB.Implications for practiceThis study's findings lay the foundation for a deeper understanding of distinct molecular mechanisms and similar treatment opportunities between upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) and had important implications for the site-specific management of patients with urothelial carcinoma. A comprehensive understanding of the biology of UTUC and UCB is needed to identify new drug targets in order to improve clinical outcomes.

Project description:We investigated the expression profiles of microRNAs (miRNA) in 26 renal cell carcinoma (RCC) FFPE tissues (3 chRCC, 5 papRCC and 18 ccRCC), 4 urothelial cell carcinomas of the upper urinary tract (UT-UCs) and 20 normal kidneys by using the miRCURY LNA™ microRNA Array, 6th gen (Exiqon, Woburn MA), containing capture probes that target all miRNAs for all species registered in the miRBASE version 16.0. Real-time PCR (qRT-PCR) using appropriate endogenous controls was performed in order to validate the microarray results of the 27 most differentially expressed (DE) miRNAs. We identified 434 miRNAs that were significantly deregulated in all tumours compared to the normal kidney tissues. Overall, 126 miRNAs (29%) showed increased expression and 303 miRNAs (69.8%) had decreased expression in RCCs and UT-UCs vs. the normal kidneys. Specifically, 374, 420, 421 and 409 miRNAs were 90% consistently down-regulated in ccRCC, papRCC, chRCC and UT-UC, respectively. Unsupervised two-way hierarchical clustering (HCL) with Euclidian distance accurately discriminated between RCC and UT-UC. Apart from one chRCC sample that was clustered with ccRCCs, HCL also managed to successfully classify the 3 RCC subtypes among them. Furthermore, it showed that ccRCC is more closely related to papRCC and that both are distinct from chRCC or UT-UC. Ninety-four miRNAs were co-upregulated among ccRCC, papRCC and chRCC; and 11, 44 and 24 miRNAs were specifically up-regulated in each one of the three RCC subtypes (ccRCC, chRCC and papRCC), respectively. On the other hand, 222 miRNAs were co-down-regulated in the three RCC subtypes, whereas 16, 18 and 5 miRNAs were specifically down-regulated in ccRCC, chRCC and papRCC, respectively. When the DE miRNAs in each RCC subtype were combined with those in UT-UC, we identified 89 and 206 miRNAs, respectively, that were up- and down-regulated in all tumor types. miRNA profiling can distinguish between RCC and UT-UC as well as among distinct RCC subtypes. Our data validicate that miRNA expression tends to be down-regulated in RCC versus the normal kidney tissue.

Project description:ObjectiveTo investigate the correlation between expression levels of adipokine and clinicopathological features and prognosis of patients with upper tract urothelial carcinoma (UTUC) based on immunohistochemical staining and bioinformatics analysis.MethodsThe 8 adipokines in this study included adiponectin (AdipoQ), leptin (LEP), interleukin (IL)-6, IL-10 and their receptors (AdipoR1, AdipoR2, LEPR, IL-6R, IL-10RA, IL-10RB). Tissue samples of patients with UTUC who underwent surgical treatment in Peking University People's Hospital from January 2014 to April 2021 were selected for immunohistochemical staining. Their quantitative gene expression data were calculated by H-Score, and relevant clinical and follow-up data were collected retrospectively. Transcription group sequencing data of UTUC patients in Gene Expression Omnibus database (GSE134292 dataset) were downloaded for comparison. Chi-square test or t-test was used to compare the expression level of adipokine between non-muscle invasive group and muscle invasive group. Univariate and multivariate Cox regression analysis and Kaplan-Meier survival curve were utilized to analyze independent predictors of overall survival (OS), disease-free survival (DFS), intravesical recurrence-free survival (IVRFS) in the both cohorts. The P < 0.05 was considered statistically significant.ResultsIn the study, 63 tissue samples of the patients with UTUC who underwent surgical treatment in Peking University People's Hospital and 57 UTUC patients in GSE134292 dataset were selected. In immunohistochemical cohort, the expressions of AdipoQ (P=0.003 6), AdipoR1 (P=0.006 5), LEP (P=0.007 7), IL-10 (P=0.006 9), and IL-10RA (P=0.008 9) were statistically higher in muscle invasive group. In GSE134292 cohort, the expressions of AdipoR1 (P=0.000 4), AdipoR2 (P=0.000 4), IL-6 (P=0.005 0), IL-10 (P=0.001 7), and IL-10RA (P=0.008 1) were statistically higher in muscle invasive group. Kaplan-Meier survival curve and multivariate Cox regression analysis showed that high IL-10RA expression was an independent predictive factor of IVRFS (P=0.044, HR=0.996, 95%CI: 0.992-0.998) in immunohistochemical cohort, which was confirmed in GSE134292 cohort (P=0.014, HR=0.515, 95%CI: 0.304-0.873).ConclusionThe expression levels of AdipoQ, AdipoR1, IL-10, and IL-10RA were correlated with tumor stage, suggesting that these adipokines played important roles in tumor progression. IL-10RA was an independent predictor of IVRFS, suggesting that IL-10 and its receptor played a critical role in tumor recurrence.

Dataset Information

Genomic Biomarkers for the Prediction of Stage and Prognosis of Upper Tract Urothelial Carcinoma.

Publications

Genomic Biomarkers for the Prediction of Stage and Prognosis of Upper Tract Urothelial Carcinoma.

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