Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy
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PROVIDER: PRJNA528124 | ENA |
REPOSITORIES: ENA
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Project description:Genomic distinctions between metastatic lower and upper tract urothelial carcinoma revealed through rapid autopsy
| PRJNA528123 | ENA
Project description:BackgroundLittle is known about the genomic differences between metastatic urothelial carcinoma (LTUC) and upper tract urothelial carcinoma (UTUC). We compare genomic features of primary and metastatic UTUC and LTUC tumors in a cohort of patients with end stage disease.MethodsWe performed whole exome sequencing on matched primary and metastatic tumor samples (N=37) from 7 patients with metastatic UC collected via rapid autopsy. Inter- and intra-patient mutational burden, mutational signatures, predicted deleterious mutations, and somatic copy alterations (sCNV) were analyzed.ResultsWe investigated 3 patients with UTUC (3 primary samples, 13 metastases) and 4 patients with LTUC (4 primary samples, 17 metastases). We found that sSNV burden was higher in metastatic LTUC compared to UTUC. Moreover, the APOBEC mutational signature was pervasive in metastatic LTUC and less so in UTUC. Despite a lower overall sSNV burden, UTUC displayed greater inter- and intra-individual genomic distances at the copy number level between primary and metastatic tumors than LTUC. Our data also indicate that metastatic UTUC lesions can arise from small clonal populations present in the primary cancer. Importantly, putative druggable mutations were found across patients with the majority shared across all metastases within a patient.ConclusionsMetastatic UTUC demonstrated a lower overall mutational burden but greater structural variability compared to LTUC. Our findings suggest that metastatic UTUC displays a greater spectrum of copy number divergence from LTUC. Importantly, we identified druggable lesions shared across metastatic samples, which demonstrate a level of targetable homogeneity within individual patients.
| S-EPMC6629128 | biostudies-literature
Project description:Genome wide DNA methylation profiling of normal and upper-tract urothelial carcinomas tissues. The Illumina Infinium EPIC arrays was used to obtain DNA methylation profiles across approximately 866,091 probes. Samples included 35 upper-tract urothelial carcinomas samples and 8 adjacent normal tissues
2020-11-30 | GSE161651 | GEO
Project description:Genome-wide methylation analysis of upper urinary tract urothelial carcinoma using Infinium MethylationEPIC BeadChip Kit
| EGAD00010002096 | EGA
Project description:DNA sequencing of 9 Taiwanese patients with upper-urinary tract urothelial cell carcinoma who are suspected of exposure to aristolochic acid
| PRJEB4138 | ENA
Project description:Genome-wide copy number analysis of upper urinary tract urothelial carcinoma using GeneChip Human Mapping 250K Nspl
| EGAD00010002098 | EGA
Project description:Prognostic biomarkers including microRNAs(miRNAs) and genes in upper tract urothelial carcinomas (UTUCs) originating from the renal pelvis and ureter account for only 5% to 10% of all UCs, but this figure is markedly higher in Taiwan, where it can reach up to 30%. By using next-generation sequencing (NGS), we analysed two pairs of renal pelvis tumours and adjacent normal urothelial tissues to screen miRNAs and messenger RNAs. By combining bioinformatics analysis from miRmap, Gene Expression Omnibus (GEO), and Oncomine and Ingenuity® Pathway Analysis databases, we identified candidate genes. To search upstream miRNAs with exact target binding sites, we used miRmap, TargetScan, and miRDB to enforce evidence. Then, we clarified gene and protein expression through an in vitro study. After interaction of the selected target genes obtained using the NGS and miRmap methods were analysed through a Venn diagram analysis, six potential genes—namely, PDE5A, RECK, ZEB2, NCALD, PLCXD3, CYBRD1—presenting significant differences were distinguished. Further analysis of gene expression indicated lower expression of that PDE5A, RECK, ZEB2, and CYBRD1 in bladder cancer tissue than in normal bladder mucosa, which indicated that PDE5A, RECK, ZEB2, and CYBRD1 may act as tumour suppressors in UTUC. In addition, we identified putative oncomiRs in miR-181c-5p target sites on PDE5A, miR-200c-3p target sites on RECK, and miR-200bc-3p/429 target sites on ZEB2. Compared with normal tissue, lower PDE5A expression in tumour specimens was demonstrated in paired UTUC tissues (normal and tumour) from 20 patients. Our findings suggest that both candidate miRNAs and regulated genes may play crucial roles in UTUC progression. We propose that these markers may be potential targets in both diagnostic and therapeutic strategies as clarified by in vitro and in vivo experiments. PDE5A also potentially presents tumour suppressor genes, as identified by comparing the expression between normal and tumour specimens from 10 patients.
2021-04-06 | GSE159824 | GEO
Project description:Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. A major hurdle to the advancement of UTUC research is the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell lines models that reflect the heterogeneity of the human disease. Models demonstrated high genomic concordance with the tumors from which they were derived with muscle-invasive tumors more likely to successfully engraft. Treatment of PDX with chemotherapy recapitulated responses observed in the patients. Analysis of a S310F HER2 mutant PDX suggested that an antibody drug conjugate targeting HER2 would have superior efficacy to HER2-selective kinase inhibitors. In sum, the biologic and phenotypic concordance between patient and PDXs suggests that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.
2020-01-29 | GSE134292 | GEO
Project description:IntroductionPrinciples of management for upper tract urothelial carcinoma (UTUC) are mostly derived from knowledge of lower tract urothelial carcinoma (LTUC), however recent research indicates that these may be disparate diseases. In this review, we sought to compare the responsiveness of these tumors to similar treatment, platinum-based chemotherapy used in the adjuvant setting.Materials and methodsPubMed, EMBASE, and Web of Science were searched using a systematic search strategy. Disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS) in patients with LTUC and UTUC treated with adjuvant chemotherapy were compared. Review Manager V 5.3 was used for meta-analyses.ResultsAdjuvant chemotherapy was associated with improved DFS (HR 0.41, 95%CI 0.31-0.54), CSS (HR 0.29, 95%CI 0.17-0.50) and OS (HR 0.51, 95%CI 0.38-0.70) rates in LTUC. The effectiveness of adjuvant chemotherapy in UTUC was less pronounced with respect to DFS (HR 0.61, 95%CI 0.1-0.93) and CSS (HR 0.70, 95%CI 0.56-0.90) rates, and there was no effect on OS (HR 0.87, 95%CI 0.69-1.10). Differences in CSS and OS were significant (p < 0.0001) in favor of adjuvant chemotherapy for LTUC versus UTUC.ConclusionDespite similar histology, we found significant differences in responsiveness to adjuvant chemotherapy between LTUC and UTUC. This may add to the already growing knowledge that these are disparate diseases. Newer systemic treatments for urothelial carcinoma may prove more effective than platinum-based chemotherapy in the adjuvant setting for UTUC.
| S-EPMC6738258 | biostudies-literature
Project description:Accurate grading and staging of upper tract urothelial carcinoma (UTUC) often proves challenging, and improved knowledge of tumor biology could identify patients who are candidates for minimally invasive therapy rather than nephroureterectomy (NU). Total RNA was extracted from formalin-fixed, paraffin-embedded NU samples. Thirty-five samples with diverse pathologies were selected and screened via microRNA RT-qPCR array for 752 unique miRNA. Validation of differentially expressed miRNA was performed on 123 additional NU tissue specimens from two institutions. The data presented in this series are for the 35 samples analyzed in the screening analysis. The data was normalized to the global mean of each sample using microRNA detected in all samples with a Cq<37.
2019-01-01 | GSE119601 | GEO