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Novel tumor subgroups of urothelial carcinoma of the bladder defined by integrated genomic analysis.

ABSTRACT: There is a need for improved subclassification of urothelial carcinoma (UC) at diagnosis. A major aim of this study was to search for novel genomic subgroups.We assessed 160 tumors for genome-wide copy number alterations and mutation in genes implicated in UC. These comprised all tumor grades and stages and included 49 high-grade stage T1 (T1G3) tumors.Our findings point to the existence of genomic subclasses of the "gold-standard" grade/stage groups. The T1G3 tumors separated into 3 major subgroups that differed with respect to the type and number of copy number events and to FGFR3 and TP53 mutation status. We also identified novel regions of copy number alteration, uncovered relationships between molecular events, and elucidated relationships between molecular events and clinico-pathologic features. FGFR3 mutant tumors were more chromosomally stable than their wild-type counterparts and a mutually exclusive relationship between FGFR3 mutation and overrepresentation of 8q was observed in non-muscle-invasive tumors. In muscle-invasive (MI) tumors, metastasis was positively associated with losses of regions on 10q (including PTEN), 16q and 22q, and gains on 10p, 11q, 12p, 19p, and 19q. Concomitant copy number alterations positively associated with TP53 mutation in MI tumors were losses on 16p, 2q, 4q, 11p, 10q, 13q, 14q, 16q, and 19p, and gains on 1p, 8q, 10q, and 12q. Significant complexity was revealed in events affecting chromosome 9.These findings may lead to improved biologic understanding and the development of prognostic biomarkers. Novel regions of copy number alteration may reveal potential therapeutic targets.

SUBMITTER: Hurst CD

PROVIDER: S-EPMC5081094 | biostudies-literature | 2012 Nov

REPOSITORIES: biostudies-literature

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Novel tumor subgroups of urothelial carcinoma of the bladder defined by integrated genomic analysis.

Hurst Carolyn D CD Platt Fiona M FM Taylor Claire F CF Knowles Margaret A MA

Clinical cancer research : an official journal of the American Association for Cancer Research 20120829 21

<h4>Purpose</h4>There is a need for improved subclassification of urothelial carcinoma (UC) at diagnosis. A major aim of this study was to search for novel genomic subgroups.<h4>Experimental design</h4>We assessed 160 tumors for genome-wide copy number alterations and mutation in genes implicated in UC. These comprised all tumor grades and stages and included 49 high-grade stage T1 (T1G3) tumors.<h4>Results</h4>Our findings point to the existence of genomic subclasses of the "gold-standard" grad ...[more]

PMID: 22932667

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Project description:BackgroundThe tumor microenvironment (TME) regulates the proliferation and metastasis of solid tumors and the effectiveness of immunotherapy against them. We investigated the prognostic role of TME-related genes based on transcriptomic data of bladder urothelial carcinoma (BLCA) and formulated a prediction model of TME-related signatures.MethodsMolecular subtypes were identified using the non-negative matrix factorization (NMF) algorithm based on TME-related genes from the TCGA database. TME-related genes with prognostic significance were screened with univariate Cox regression analysis and lasso regression. Nomogram was developed based on risk genes. Receiver operating characteristic (ROC) curve and decision curve analysis (DCA) were used for inner and outer validation of the model. Risk scores (RS) of patients were calculated and divided into high-risk group (HRG) and low-risk group (LRG) to compare the differences in clinical characteristics and PD-L1 treatment responsiveness between HRG and LRG.ResultsWe identified two molecular subtypes (C1 and C2) according to the NMF algorithm. There were significant differences in overall survival (OS) (p<0.05), progression-free survival (PFS) (p<0.05), and immune cell infiltration between the two subtypes. A total of eight TME-associated genes (CABP4, ZNF432, BLOC1S3, CXCL11, ANO9, OAS1, FBN2, CEMIP) with independent prognostic significance were screened to build prognostic risk models. Age (p<0.001), grade (p<0.001), and RS (p<0.001) were independent predictors of survival in BLCA patients. The developed RS nomogram was able to predict the prognosis of BLCA patients at 1, 3, and 5 years more potentially than the models of other investigators according to ROC and DCA. RS showed significantly higher values (p = 0.047) in patients with stable disease (SD)/progressive disease (PD) compared to patients with complete response (CR)/partial response (PR).ConclusionsWe successfully clustered and constructed predictive models for TME-associated genes and helped guide immunotherapy strategies.

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:BackgroundUrothelial carcinoma of the bladder (UCB) is the most prevalent malignant tumor of the urinary system worldwide, which has a significant recurrence rate despite multiple treatment options available. As a unique and novel copper-dependent programmed cell death mechanism, the comprehensive impact of cuproptosis on the tumor immune microenvironment, clinicopathological characteristics and the prognosis of patients remains largely unclear.MethodsA total of 568 UCB samples were thoroughly examined for cuproptosis patterns using data downloaded from TCGA and GEO, based on 10 cuproptosis-related genes reported previously. Then, the univariate COX regression analysis was performed on the genes that differed across the various patterns. To measure individual cuproptosis pattern, a cuproptosis score system was constructed using a principal component analysis algorithm. To validate the scoring system, immunohistochemical staining was performed on tumor tissues with different pathological grades, and experiments in vitro were conducted about the differentially expressed genes related to prognosis. Finally, the capacity of scoring system to predict the response to immunotherapy was verified by using data from IMvigor 210 cohort.ResultsFour unique cuproptosis clusters and two gene clusters were finally found by the investigation. The clinical features and prognosis of patients, as well as the mRNA transcriptome, pathway enrichment, and immune cell infiltration in TME, varied dramatically between various cuproptosis clusters and gene clusters. To identify individual cuproptosis patterns in UCB patients, we also established a cuproptosis scoring system. After validation with multiple methods, it was indicated that the score system could predict the prognosis of UCB patients and was significantly connected to clinical features such TNM category, tumor grade, molecular type and ultimate survival status. The clinical outcomes of UCB patients were predicted effectively according to the tumor mutation burden in conjunction with the scoring system. Furthermore, we found that the cuproptosis score had a significant correlation with the response to immunotherapy and the sensitivity to chemotherapy.ConclusionThis study revealed the potential impact of cuproptosis on the UCB tumor immune microenvironment and clinical pathological characteristics. The cuproptosis score system could effectively predict the prognosis of patients and the response to chemotherapy and immunotherapy.

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Novel tumor subgroups of urothelial carcinoma of the bladder defined by integrated genomic analysis.

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Novel tumor subgroups of urothelial carcinoma of the bladder defined by integrated genomic analysis.

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