Predictive value of clinicopathological markers for the metachronous bladder cancer and prognosis of upper tract urothelial carcinoma.
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ABSTRACT:
SUBMITTER: Feng C
PROVIDER: S-EPMC3915316 | biostudies-other | 2014
REPOSITORIES: biostudies-other
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Project description:This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.
| S-EPMC7935810 | biostudies-literature
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.
| S-EPMC9385515 | biostudies-literature
Project description:This study aimed to assess the prognostic significance of pre-treatment lymphocyte-related systemic inflammatory biomarkers in upper tract urothelial carcinoma (UTUC) patients. This study included non-metastatic UTUC patients treated at our hospital between 2001 and 2013. The receiver operating characteristic curve was used to obtain the optimal neutrophile-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII). Multivariate logistic regression was performed to investigate the relationship between NLR, PLR, and SII and clinical pathologic characteristics. The Kaplan-Meier method was used to calculate the metastasis-free survival (MFS), cancer-specific survival (CSS), and bladder recurrence-free survival (BRFS), and the log-rank test was used to compare the survival rate. Overall, 376 patients were included in the current study. An elevated SII was associated with symptomatic hydronephrosis, bladder cancer history, advanced pathologic tumor stage, lymph node invasion, adjuvant chemotherapy and concomitant carcinoma in situ (CIS); high NLR was associated with older age, symptomatic hydronephrosis, hemodialysis status, anemia, multifocal tumor, advanced pathologic tumor stage, and adjuvant chemotherapy; and high PLR was associated with older age, anemia, advanced pathologic tumor stage, and adjuvant chemotherapy. The Kaplan-Meier analysis indicated that patients exhibiting higher NLR, PLR, and SII showed significantly poor MFS and CSS rates. Only high SII showed significantly worse BRFS rates. The NLR, PLR, and SII were independent predictive factors for both MFS and CSS in UTUC patients. Among the factors, only elevated SII can predict bladder recurrence. Therefore, the patients might need close bladder monitoring during the follow-up.
| S-EPMC8623909 | biostudies-literature
Project description:Urothelial carcinoma (UC), arising from the urothelium of the urinary tract, can occur in the upper (UTUC) and the urinary bladder (UBUC). A representative molecular aberration for UC characteristics and prognosis remains unclear. Data mining of Gene Expression Omnibus focusing on UBUC, we identified sulfatase-1 (SULF1) upregulation is associated with UC progression. SULF1 controls the sulfation status of heparan sulfate proteoglycans and plays a role in tumor growth and metastasis, while its role is unexplored in UC. To first elucidate the clinical significance of SULF1 transcript expression, real-time quantitative RT-PCR was performed in a pilot study of 24 UTUC and 24 UBUC fresh samples. We identified that increased SULF1 transcript abundance was associated with higher primary tumor (pT) status. By testing SULF1 immunoexpression in independent UTUC and UBUC cohorts consisted of 340 and 295 cases, respectively, high SULF1 expression was significantly associated with advanced pT and nodal status, higher histological grade and presence of vascular invasion in both UTUC and UBUC. In multivariate survival analyses, high SULF1 expression was independently associated with worse DSS (UTUC hazard ratio [HR] = 3.574, P < 0.001; UBUC HR = 2.523, P = 0.011) and MeFS (UTUC HR = 3.233, P < 0.001; UBUC HR = 1.851, P = 0.021). Furthermore, depletion of SULF1 expression by using RNA interference leaded to impaired cell proliferative, migratory, and invasive abilities in vitro. In addition, we further confirmed oncogenic role of SULF1 with gain-of function experiments. In conclusion, our findings implicate the oncogenic role of SULF1 expression in UC, suggesting SULF1 as a prognostic and therapeutic target of UC.
| S-EPMC5564558 | biostudies-literature
Project description:Upper tract urothelial carcinoma (UTUC) is a relatively uncommon and poorly investigated malignancy, however, bladder recurrence after radical nephroureterectomy (RNU) is a frequent event. In this review, we summarize the current knowledge on risk prediction of bladder tumor recurrence after RNU, including surgical strategies and adjuvant intravesical treatments to reduce the risk of recurrence. Finally, we outline some of the more recent advances in genomics that will likely lead to new prognostic markers and risk stratification tools that may refine UTUC treatment in the future.
| S-EPMC7475654 | biostudies-literature
Project description:Background and aimsOncogenesis is a multistep process, resulting from the accumulations of multiple mutations. Of these mutations, self-sufficiency in growth signals, i.e., disruption of cell growth regulation, is the first episode. Nonetheless, the genes associated with cell growth dysregulation have seldom been systematically evaluated in either urothelial carcinomas of upper urinary tract (UTUC) or urothelial carcinomas of urinary baldder (UBUC). By data mining a published transcriptomic dataset of UBUCs (GSE31684), we identified the NDN gene as one of the most significant of those associated with the regulation of cell growth and found this gene is associated with advanced tumor status and metastatic disease (GO:0001558). Accordingly, we analyzed NDN transcript and protein expression with their clinicopathological significance.Materials and methodsWe used real time RT-PCR to detect NDN transcript levels in 27 UTUCs and 27 UBUCs, respectively. Immunohistochemical study was performed to determine NDN protein (a.k.a. Necdin) expression evaluated by H-score method in 340 UTUCs and 295 UBUCs. NDN expression was further correlated with clinicopathological features and disease-specific survival (DSS) and metastasis-free survival (MeFS).ResultsNDN transcriptional level was significantly higher in UCs of both sites with stepwise more advanced pT statuses. Through immunohistochemistry, we found NDN protein expression was significantly associated with adverse clinicopathological parameters, e.g., advanced pT status, nodal metastasis, high grade histological patterns, and frequent mitotses (all P<0.05). In univariate analysis, NDN overexpression not only predicted worse DSS and MeFS in both the UTUC and UBUC groups, it also served as an independent prognostic factor for DSS and MeFS in multivariate analysis (all P<0.05).ConclusionsNDN may play an important role in tumor progression in UC and could serve as a prognostic biomarker and a potential novel therapeutic target in UC.
| S-EPMC4747885 | biostudies-literature
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.
| S-EPMC8342585 | biostudies-literature
Project description:PURPOSE:To investigate genomic differences between urothelial carcinomas of the upper tract (UTUC) and bladder (UCB), with a focus on defining the clonal relatedness of temporally distinct tumors. EXPERIMENTAL DESIGN:We prospectively sequenced tumors and matched germline DNA using targeted next-generation sequencing methods. The cohort included 195 UTUC patients and 454 UCB patients. For a subgroup of 29 patients with UTUC and a history of a subsequent UCB, both tumors were analyzed to assess their clonal relatedness. RESULTS:With the progression to higher UTUC clinical state, there were fewer alterations in the RTK/RAS pathway but more alterations in TP53/MDM2. Compared with UCB, TP53, RB1, and ERBB2 were less frequently altered in UTUC (26% vs. 46%, 3% vs. 20%, 8% vs. 19%, respectively; Q < 0.001), whereas FGFR3 and HRAS were more frequently altered (40% vs. 26%, 12% vs. 4%, respectively; Q < 0.001). On the basis of an integrated analysis of tumor mutational burden, MSIsensor score and mutational signature, 7.2% of UTUC tumors were classified as MSI-high/MMR-deficient (MSI-H/dMMR). The risk of bladder recurrence after UTUC was significantly associated with mutations in FGFR3, KDM6A, CCND1, and TP53. Comparison of UCB with corresponding UTUC tumors from the same patient supports their clonal relatedness. CONCLUSIONS:UTUC and UCB exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumors, UCB and UTUC were always clonally related. Genomic characterization of UTUC provides information regarding the risk of bladder recurrence and can identify tumors associated with Lynch syndrome.
| S-EPMC6359971 | biostudies-literature
Project description:PURPOSE:A better understanding of the molecular basis of urothelial carcinoma (UC) is needed to refine the clinical decision-making process. METHODS AND MATERIALS:We performed next-generation sequencing to investigate the mutational and transcriptional profiles of commonly mutated genes in UC using Ampliseq v2. Copy number variations (CNVs) were detected with nCounter assay. Genetic alterations between upper tract UC (UTUC) and urinary bladder UC (UBUC) were compared. RESULTS:Tumor samples from 31 UTUC and 61 UBUC patients were included in analysis. The two groups showed similar clinicopathologic features including tumor grade and stage. Median survival was longer in UTUC than UBUC patients, though this was statistically nonsignificant (59 vs 41 months, P=.137). In total, we found 982 genetic alterations from 92 samples: single nucleotide variants were the most common type of somatic mutation (479/508, 94.3%). Frequently detected somatic mutations included TP53 (68.5%), KDR (41.3%), and PIK3CA (17.4%). Notably, RB1 mutations were the only mutations significantly different between the UBUC and UTUC groups (19.7% vs. 0%, P=.020). The most common types of CNVs included amplifications (56/62, 90.3%): 17.7% of patients identified amplifications in NOTCH1. We also identified five translocations in the entire study population, including one case with FGFR3-TACC3 (Chr4) fusion. CONCLUSION:Within a small study population, we identified similar genetic alterations in both UTUC and UBUC patients, indicating a basis for similar management strategies.
| S-EPMC5699894 | biostudies-literature
Project description:Background: The TP53 tumor suppressor gene plays a crucial role in the carcinogenesis of many malignancies, including urothelial carcinoma (UC). Overexpression of p53 is associated with poor prognosis in UC. Recently, RING finger protein 128 (RNF128) was shown to be involved in p53-induced apoptosis, forming a negative feedback loop. However, the significance of RNF128 in patients with UC remains unknown. In this study, our aim was to evaluate the expression of RNF128 in UC and to assess its predictive and prognostic value in a well-established cohort. Methods: Through data mining from a published transcriptome (GSE31684), RNF128 was identified as the most differentially expressed gene in UC among those associated with negative regulation of the cytokine biosynthetic process (GO:0042036). Its immunoexpression was further evaluated using the H-scores of 340 patients with upper urinary tract UC (UTUC) and 295 with urinary bladder UC (UBUC). The scores were correlated with clinicopathological features, disease-specific survival (DSS) and metastasis-free survival (MeFS). We also used Western blot analysis to evaluate RNF128 protein expression in human urothelial cell (HUC) lines. Results: Downregulation of RNF128 expression was significantly associated with advanced pT stage (p<0.001), high histological grade (UTUC, p<0.001; UBUC, p=0.035), nodal metastasis (UTUC, p<0.001; UBUC, p=0.001), vascular invasion (UTUC, p<0.001; UBUC, p=0.008) and high mitotic rate (UTUC, p=0.003; UBUC, p=0.023). Low expression of RNF128 was an adverse prognosticator for DSS (UTUC, p<0.0001; UBUC, p<0.0001) and MeFS (UTUC, p<0.0001; UBUC, p=0.0002). Moreover, low expression was predictive of poor DSS (UTUC, p=0.006; UBUC, p=0.003) and MeFS (UTUC, p=0.009; UBUC, p=0.036) in multivariate comparisons. Western blot analysis showed that the RNF128 protein was downregulated in invasive urothelial cancer cell lines. Conclusion: Our findings showed that downregulation of RNF128 was correlated with cancer invasiveness and metastasis as well as reduced survival in patients with UTUC and UBUC, identifying RNF128 as a prognostic factor in UC.
| S-EPMC5166527 | biostudies-literature